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Disclosed herein are compounds of Formula (I), (II), and (III)
pharmaceutical compositions comprising the same, methods of modulating
the activity a thrombopoietin receptor using the same, methods of
identifying compounds as thrombopoietin receptor modulators, and methods
of treating disease by administering a compound of the invention to a
patient in need thereof.

1. A compound of Formula I: or a pharmaceutically acceptable salt, ester,
amide, or prodrug thereof, wherein: R.sup.1 is selected from
CO.sub.2R.sup.10, CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a carboxylic
acid bioisostere; R.sup.2 and R.sup.3 are each independently selected
from null, hydrogen, OR.sup.12, NR.sup.12R.sup.13, an optionally
substituted C.sub.1-C.sub.4 aliphatic, an optionally substituted
C.sub.1-C.sub.4 haloaliphatic, an optionally substituted C.sub.1-C.sub.4
heteroaliphatic, an optionally substituted ring, and
(CH.sub.2).sub.mR.sup.14; or R.sup.2 and R.sup.3 taken together form an
optionally substituted olefin; or R.sup.2 and R.sup.3 are linked to form
an optionally substituted C.sub.3-C.sub.8 ring; R.sup.4 is selected from
hydrogen, F, Cl, Br, C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4
haloaliphatic, C.sub.1-C.sub.4 heteroaliphatic, and a ring; R.sup.5is
selected from hydrogen, OR.sup.10, SR.sup.10, NHR.sup.11, and CO.sub.2H;
R.sup.6 is selected from hydrogen, OR.sup.12, NR.sup.12R.sup.13, F, Cl,
Br, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
heteroalkyl, and a ring; R.sup.7 is selected from hydrogen, an optionally
substituted C.sub.1-C.sub.8 aliphatic, an optionally substituted
C.sub.1-C.sub.8 haloaliphatic, an optionally substituted C.sub.1-C.sub.8
heteroaliphatic, an optionally substituted C.sub.1-C.sub.8
heterohaloaliphatic, an optionally substituted ring, and
(CH.sub.2).sub.mR.sup.14; R.sup.10 is selected from hydrogen, an
optionally substituted C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4
haloaliphatic, C.sub.1-C.sub.4 heteroaliphatic, and a ring; R.sup.11 is
selected from hydrogen, SO.sub.2R.sup.15, C.sub.1-C.sub.4 aliphatic,
C.sub.1-C.sub.4 haloaliphatic, C.sub.1-C.sub.4 heteroaliphatic, and a
ring; R.sup.12 and R.sup.13 are each independently selected from
hydrogen, an optionally substituted C.sub.1-C.sub.4 aliphatic, an
optionally substituted C.sub.1-C.sub.4 haloaliphatic, an optionally
substituted C.sub.1-C.sub.4 heteroaliphatic, an optionally substituted
ring, and (CH.sub.2).sub.mR.sup.14; or one of R.sup.12 and R.sup.13 is an
optionally substituted C.sub.2-C.sub.6 aliphatic or an optionally
substituted ring and the other of R.sup.12 and R.sup.13 is null; or
R.sup.12 and R.sup.13 are linked to form an optionally substituted
C.sub.3-C.sub.8 ring; R.sup.14 is selected from an optionally substituted
aryl and an optionally substituted heteroaryl; R.sup.15 is selected from
hydrogen, C.sub.1-C.sub.3 aliphatic, C.sub.1-C.sub.3 haloaliphatic, and a
ring; Y is a 1-4 atom spacer comprising one or more groups selected from
an optionally substituted C.sub.1-C.sub.6 aliphatic, an optionally
substituted C.sub.1-C.sub.6 heteroaliphatic, an optionally substituted
phenyl, an optionally substituted heteroaryl, an optionally substituted
C.sub.3-C.sub.5 heterocycle, and an optionally substituted alicyclic,
provided that Y is not --N.dbd.CR.sup.6-- orientated to form a
dihydropyrazole; Z is selected from: a 2-5 atom spacer selected from an
optionally substituted C.sub.6-C.sub.10 aryl and an optionally
substituted C.sub.1-C.sub.8 heteroaryl, and a 1-5 atom spacer of selected
from an optionally substituted C.sub.1-C.sub.6 aliphatic, an optionally
substituted C.sub.1-C.sub.6 heteroaliphatic, and an optionally
substituted C.sub.1-C.sub.6 haloaliphatic; m is 0, 1, or 2; and n is 0 or
1.

2. A compound of claim 1, wherein: R.sup.1 is selected from
CO.sub.2R.sup.10, CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a carboxylic
acid bioisostere selected from tetrazole, NHSO.sub.2R.sup.15,
OC(S)NR.sup.10R.sup.11, SC(O)NR.sup.10R.sup.11, and wherein A, B, and C
are each independently selected from O, S, and N; R.sup.2 and R.sup.3 are
each independently selected from hydrogen, OR.sup.12, NR.sup.12R.sup.13,
an optionally substituted C.sub.1-C.sub.4 alkyl, an optionally
substituted C.sub.1-C.sub.4 haloalkyl, an optionally substituted
C.sub.1-C.sub.4 heteroalkyl, an optionally substituted ring, and
(CH.sub.2).sub.mR.sup.14; or R.sup.2 and R.sup.3 taken together form an
optionally substituted olefin; or R.sup.2 and R.sup.3 are linked to form
an optionally substituted C.sub.3-C.sub.8 ring; R.sup.4 is selected from
hydrogen, F, Cl, Br, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 heteroalkyl, and a non-aromatic ring; R.sup.7is selected
from hydrogen, an optionally substituted C.sub.1-C.sub.8 alkyl, an
optionally substituted C.sub.1-C.sub.8 haloalkyl, an optionally
substituted C.sub.1-C.sub.8 heteroalkyl, an optionally substituted
C.sub.1-C.sub.8 heterohaloalkyl, an optionally substituted aromatic ring,
and (CH.sub.2).sub.mR.sup.14; R.sup.10 is selected from hydrogen, an
optionally substituted C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 heteroalkyl, and a non-aromatic ring; R.sup.11 is
selected from hydrogen, SO.sub.2R.sup.15, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 heteroalkyl, and a
non-aromatic ring; R.sup.12 and R.sup.13 are each independently selected
from hydrogen, an optionally substituted C.sub.1-C.sub.4 alkyl, an
optionally substituted C.sub.1-C.sub.4 haloalkyl, an optionally
substituted C.sub.1-C.sub.4 heteroalkyl, an optionally substituted
non-aromatic ring, and (CH.sub.2).sub.mR.sup.14; or one of R.sup.12 and
R.sup.13 is an optionally substituted C.sub.2-C.sub.6 alkyl or an
optionally substituted non-aromatic ring, and the other of R.sup.12 and
R.sup.13 is null; or R.sup.12 and R.sup.13 are linked to form an
optionally substituted C.sub.3-C.sub.8 ring; R.sup.15 is selected from
hydrogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, and aryl; Y
is a 1-4 atom spacer comprising one or more groups selected from an
optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted
C.sub.1-C.sub.6 heteroalkyl, an optionally substituted C.sub.2-C.sub.6
alkenyl, an optionally substituted C.sub.2-C.sub.6 heteroalkenyl, an
optionally substituted phenyl, an optionally substituted heteroaryl, an
optionally substituted C.sub.3-C.sub.5 heterocycle, an optionally
substituted cycloalkyl, and an optionally substituted cycloalkenyl; and Z
is selected from: a 2-5 atom spacer selected from an optionally
substituted C.sub.6-C.sub.10 aryl and an optionally substituted
C.sub.1-C.sub.8 heteroaryl, and a 1-5 atom spacer of selected from an
optionally substituted C.sub.1-C.sub.6 alkyl, an optionally substituted
C.sub.1-C.sub.6 heteroalkyl, an optionally substituted C.sub.1-C.sub.6
haloalkyl, an optionally substituted C.sub.2-C.sub.6 alkenyl, an
optionally substituted C.sub.2-C.sub.6 heteroalkenyl, an optionally
substituted C.sub.2-C.sub.6 haloalkenyl, an optionally substituted
C.sub.2-C.sub.6 alkynyl, and an optionally substituted C.sub.2-C.sub.6
heteroalkyl.

3. A compound of claim 1 wherein Y is a 1-4 atom spacer comprising at
least one of: an optionally substituted C.sub.1-C.sub.6 alkyl, an
optionally substituted C.sub.1-C.sub.6 heteroalkyl, an optionally
substituted C.sub.2-C.sub.6 alkenyl, and an optionally substituted
C.sub.2-C.sub.6 heteroalkenyl; and at least one of: an optionally
substituted phenyl an optionally substituted heteroaryl, an optionally
substituted C.sub.3-C.sub.5 heterocycle, an optionally substituted
cycloalkyl; and an optionally substituted cycloalkenyl.

4. A compound of Formula II: or a pharmaceutically acceptable salt,
ester, amide, or prodrug thereof, wherein: R.sup.1 is selected from
CO.sub.2R.sup.10, CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a carboxylic
acid bioisostere; R.sup.2 and R.sup.3 are each independently selected
from null, hydrogen, OR.sup.12, NR.sup.12R.sup.13, an optionally
substituted C.sub.1-C.sub.4 aliphatic, an optionally substituted
C.sub.1-C.sub.4 haloaliphatic, an optionally substituted C.sub.1-C.sub.4
heteroaliphatic, an optionally substituted ring, and
(CH.sub.2).sub.mR.sup.14; or R.sup.2 and R.sup.3 taken together form an
optionally substituted olefin; or R.sup.2 and R.sup.3 are linked to form
an optionally substituted C.sub.3-C.sub.8 ring; R.sup.4is selected from
hydrogen, F, Cl, Br, C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4
haloaliphatic, C.sub.1-C.sub.4 heteroaliphatic, and a ring; R.sup.5 is
selected from hydrogen, OR.sup.10, SR.sup.10, NHR.sup.11, and CO.sub.2H;
R.sup.6 is selected from hydrogen, OR.sup.12, NR.sup.12R.sup.13, F, Cl,
Br, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
heteroalkyl, and a ring; R.sup.7 is selected from hydrogen, an optionally
substituted C.sub.1-C.sub.8 aliphatic, an optionally substituted
C.sub.1-C.sub.8 haloaliphatic, an optionally substituted C.sub.1-C.sub.8
heteroaliphatic, an optionally substituted C.sub.1-C.sub.8
heterohaloaliphatic, an optionally substituted ring, and
(CH.sub.2).sub.mR.sup.14; R.sup.8 and R.sup.9 are each independently
selected from hydrogen, F, Cl, Br, CO.sub.2R.sup.10, NO.sub.2, CN,
SO.sub.2R.sup.10, (CH.sub.2).sub.mR.sup.14, C.sub.1-C.sub.4 aliphatic,
C.sub.1-C.sub.4 haloaliphatic, C.sub.1-C.sub.4 heteroaliphatic,
C.sub.1-C.sub.4 heterohaloaliphatic, and a ring; R.sup.10 is selected
from hydrogen, an optionally substituted C.sub.1-C.sub.4 aliphatic,
C.sub.1-C.sub.4 haloaliphatic, C.sub.1-C.sub.4 heteroaliphatic, and a
ring; R.sup.11 is selected from hydrogen, SO.sub.2R.sup.15,
C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4 haloaliphatic, C.sub.1-C.sub.4
heteroaliphatic, and a ring; R.sup.12 and R.sup.13 are each independently
selected from hydrogen, an optionally substituted C.sub.1-C.sub.4
aliphatic, an optionally substituted C.sub.1-C.sub.4 haloaliphatic, an
optionally substituted C.sub.1-C.sub.4 heteroaliphatic, an optionally
substituted ring, and (CH.sub.2).sub.mR.sup.14; or one of R.sup.12 and
R.sup.13 is an optionally substituted C.sub.2-C.sub.6 aliphatic or an
optionally substituted ring and the other of R.sup.12 and R.sup.13 is
null; or R.sup.12 and R.sup.13 are linked to form an optionally
substituted C.sub.3-C.sub.8 ring; R.sup.14 is selected from an optionally
substituted aryl and an optionally substituted heteroaryl; R.sup.15 is
selected from hydrogen, C.sub.1-C.sub.3 aliphatic, C.sub.1-C.sub.3
haloaliphatic, and a ring; Q is selected from O and S; X is selected from
O, S, NR.sup.10, and CR.sup.10R.sup.10; Y is selected from: Z is
selected from: a 2-5 atom spacer selected from an optionally substituted
C.sub.6-C.sub.10 aryl and an optionally substituted C.sub.1-C.sub.8
heteroaryl, and a 1-5 atom spacer of selected from an optionally
substituted C.sub.1-C.sub.6 aliphatic, an optionally substituted
C.sub.1-C.sub.6 heteroaliphatic, and an optionally substituted
C.sub.1-C.sub.6 haloaliphatic; m is 0, 1, or 2; and n is 0 or 1.

5. A compound of claim 4 wherein: R.sup.1 is selected from
CO.sub.2R.sup.10, CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a carboxylic
acid bioisostere selected from tetrazole, NHSO.sub.2R .sup.5,
OC(S)NR.sup.10R.sup.11, SC(O)NR.sup.10R.sup.11, and wherein A, B, and C
are each independently selected from O, S, and N; R.sup.2 and R.sup.3 are
each independently selected from hydrogen, OR.sup.12, NR.sup.12R.sup.13,
an optionally substituted C.sub.1-C.sub.4 alkyl, an optionally
substituted C.sub.1-C.sub.4 haloalkyl, an optionally substituted
C.sub.1-C.sub.4 heteroalkyl, an optionally substituted ring, and
(CH.sub.2).sub.mR.sup.14; or R.sup.2 and R.sup.3 taken together form an
optionally substituted olefin; or R.sup.2 and R.sup.3 are linked to form
an optionally substituted C.sub.3-C.sub.8 ring; or one of R2 or R3 is
null and the other is R.sup.4 is selected from hydrogen, F, Cl, Br,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, and C.sub.1-C.sub.4
heteroalkyl and a non-aromatic ring; R.sup.7 is selected from hydrogen,
an optionally substituted C.sub.1-C.sub.8 alkyl, an optionally
substituted C.sub.1-C.sub.8 haloalkyl, an optionally substituted
C.sub.1-C.sub.8 heteroalkyl, an optionally substituted C.sub.1-C.sub.8
heterohaloalkyl, an optionally substituted aromatic ring, and
(CH.sub.2).sub.mR.sup.14; R.sup.8 and R.sup.9 are each independently
selected from hydrogen, F, Cl, Br, CO.sub.2 R.sup.10, NO.sub.2, CN,
SO.sub.2R.sup.10, (CH.sub.2).sub.mR.sup.14, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 heteroalkyl, C.sub.1-C.sub.4
heterohaloalkyl, and a ring; R.sup.10 is selected from hydrogen, an
optionally substituted C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 heteroalkyl, and a non-aromatic ring; R.sup.11 is
selected from hydrogen, SO.sub.2R.sup.15, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, and C.sub.1-C.sub.4 heteroalkyl; R.sup.12 and
R.sup.13 are each independently selected from hydrogen, an optionally
substituted C.sub.1-C.sub.4 alkyl, an optionally substituted
C.sub.1-C.sub.4 haloalkyl, an optionally substituted C.sub.1-C.sub.4
heteroalkyl, an optionally substituted non-aromatic ring, and
(CH.sub.2).sub.mR.sup.14; or one of R.sup.12 and R.sup.13 is an
optionally substituted C.sub.2-C.sub.6 alkyl or an optionally substituted
non-aromatic ring and the other of R.sup.12 and R.sup.13 is null; or
R.sup.12 and R.sup.13 are linked to form an optionally substituted
C.sub.3-C.sub.8 ring; R.sup.15 is selected from hydrogen, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl, and aryl; and Z is selected from: a 2-5
atom spacer selected from an optionally substituted C.sub.6-C.sub.10 aryl
and an optionally substituted C.sub.1-C.sub.8 heteroaryl, and a 1-5 atom
spacer of selected from an optionally substituted C.sub.1-C.sub.6 alkyl,
an optionally substituted C.sub.1-C.sub.6 heteroalkyl, an optionally
substituted C.sub.1-C.sub.6 haloalkyl, an optionally substituted
C.sub.2-C.sub.6 alkenyl, an optionally substituted C.sub.2-C.sub.6
heteroalkenyl, an optionally substituted C.sub.2-C.sub.6 haloalkenyl, an
optionally substituted C.sub.2-C.sub.6 alkynyl, and an optionally
substituted C.sub.2-C.sub.6 heteroalkyl.

6. A compound of claim 4, wherein Y is a 1-4 atom spacer comprising at
least one of: an optionally substituted C.sub.1-C.sub.6 alkyl, an
optionally substituted C.sub.1-C.sub.6 heteroalkyl, an optionally
substituted C.sub.2-C.sub.6 alkenyl, and an optionally substituted
C.sub.2-C.sub.6 heteroalkenyl; and at least one of: an optionally
substituted phenyl an optionally substituted heteroaryl, an optionally
substituted C.sub.3-C.sub.5 heterocycle, an optionally substituted
cycloalkyl; and an optionally substituted cycloalkenyl.

7. A compound of Formula III: or a pharmaceutically acceptable salt,
ester, amide, or prodrug thereof, wherein: R.sup.1 is selected from
CO.sub.2R.sup.10, CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a carboxylic
acid bioisostere; R.sup.2 and R.sup.3 are each independently selected
from null, hydrogen, OR.sup.12, NR.sup.12R.sup.13, an optionally
substituted C.sub.1-C.sub.4 aliphatic, an optionally substituted
C.sub.1-C.sub.4 haloaliphatic, an optionally substituted C.sub.1-C.sub.4
heteroaliphatic, an optionally substituted ring, and
(CH.sub.2).sub.mR.sup.14; or R.sup.2 and R.sup.3 taken together form an
optionally substituted olefin; or R.sup.2 and R.sup.3 are linked to form
an optionally substituted C.sub.3-C.sub.8 ring; R.sup.4 is selected from
hydrogen, F, Cl, Br, C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4
haloaliphatic, C.sub.1-C.sub.4 heteroaliphatic, and a ring; R.sup.5 is
selected from hydrogen, OR.sup.10, SR.sup.10, NHR.sup.11, and CO.sub.2H;
R.sup.6 is selected from hydrogen, OR.sup.12, NR.sup.12R.sup.13, F, Cl,
Br, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, and C.sub.1-C.sub.4
heteroalkyl; R.sup.7is selected from hydrogen, an optionally substituted
C.sub.1-C.sub.8 aliphatic, an optionally substituted C.sub.1-C.sub.8
haloaliphatic, an optionally substituted C.sub.1-C.sub.8 heteroaliphatic,
an optionally substituted C.sub.1-C.sub.8 heterohaloaliphatic, an
optionally substituted ring, and (CH.sub.2).sub.mR.sup.14; R.sup.8 and
R.sup.9 are each independently selected from hydrogen, F, Cl, Br,
CO.sub.2R.sup.10, NO.sub.2, CN, SO.sub.2R.sup.10,
(CH.sub.2).sub.mR.sup.14, C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4
haloaliphatic, C.sub.1-C.sub.4 heteroaliphatic, and C.sub.1-C.sub.4
heterohaloaliphatic; R.sup.10 is selected from hydrogen, an optionally
substituted C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4 haloaliphatic,
C.sub.1-C.sub.4 heteroaliphatic, and a ring; R.sup.11 is selected from
hydrogen, SO.sub.2R.sup.15, C.sub.1-C.sub.4 aliphatic, C.sub.1-C.sub.4
haloaliphatic, C.sub.1-C.sub.4 heteroaliphatic, and a ring; R.sup.12 and
R.sup.13 are each independently selected from hydrogen, an optionally
substituted C.sub.1-C.sub.4 aliphatic, an optionally substituted
C.sub.1-C.sub.4 haloaliphatic, an optionally substituted C.sub.1-C.sub.4
heteroaliphatic, an optionally substituted ring, and
(CH.sub.2).sub.mR.sup.14; or one of R.sup.12 and R.sup.13 is an
optionally substituted C.sub.2-C.sub.6 aliphatic or an optionally
substituted ring and the other of R.sup.12 and R.sup.13 is null; or
R.sup.12 and R.sup.13 are linked to form an optionally substituted
C.sub.3-C.sub.8 ring; R.sup.14 is selected from an optionally substituted
aryl and an optionally substituted heteroaryl; R.sup.15 is selected from
hydrogen, C.sub.1-C.sub.3 aliphatic, C.sub.1-C.sub.3 haloaliphatic, and a
ring; m is 0, 1, or 2; and n is 0 or 1.

8. A compound of claim 7 wherein: R.sup.1 is selected from
CO.sub.2R.sup.10, CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a carboxylic
acid bioisostere selected from tetrazole, NHSO.sub.2R.sup.15,
OC(S)NR.sup.10R.sup.11, SC(O)NR.sup.10R.sup.11, and wherein A, B, and C
are each independently selected from O, S, and N; R.sup.2 and R.sup.3 are
each independently selected from hydrogen, OR.sup.12, NR.sup.12R.sup.13,
an optionally substituted C.sub.1-C.sub.4 alkyl, an optionally
substituted C.sub.1-C.sub.4 haloalkyl, an optionally substituted
C.sub.1-C.sub.4 heteroalkyl, an optionally substituted ring, and
(CH.sub.2).sub.mR.sup.14; or R.sup.2 and R.sup.3 taken together form an
optionally substituted olefin; or R.sup.2 and R.sup.3 are linked to form
an optionally substituted C.sub.3-C.sub.8 ring; R.sup.4is selected from
hydrogen, F, Cl, Br, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 heteroalkyl, and a non-aromatic ring; R.sup.7is selected
from hydrogen, an optionally substituted C.sub.1-C.sub.8 alkyl, an
optionally substituted C.sub.1-C.sub.8 haloalkyl, an optionally
substituted C.sub.1-C.sub.8 heteroalkyl, an optionally substituted
C.sub.1-C.sub.8 heterohaloalkyl, an optionally substituted aromatic ring,
and (CH.sub.2).sub.mR.sup.14; R.sup.8 and R.sup.9 are each independently
selected from hydrogen, F, Cl, Br, CO.sub.2R.sup.10, NO.sub.2, CN,
SO.sub.2R.sup.10, (CH.sub.2).sub.mR .sup.4, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 heteroalkyl, and
C.sub.1-C.sub.4 heterohaloalkyl; R.sup.10 is selected from hydrogen, an
optionally substituted C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 heteroalkyl and a non-aromatic ring; R.sup.11 is selected
from hydrogen, SO.sub.2R.sup.15, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
haloalkyl, and C.sub.1-C.sub.4 heteroalkyl, and a non-aromatic ring;
R.sup.12 and R.sup.13 are each independently selected from hydrogen, an
optionally substituted C.sub.1-C.sub.4 alkyl, an optionally substituted
C.sub.1-C.sub.4 haloalkyl, an optionally substituted C.sub.1-C.sub.4
heteroalkyl, a non-aromatic ring, and (CH.sub.2).sub.mR.sup.14; or one of
R.sup.12 and R.sup.13 is an optionally substituted C.sub.2-C.sub.6 alkyl
or a non-aromatic ring, and the other of R.sup.12 and R.sup.13 is null;
or R.sup.12 and R.sup.13 are linked to form an optionally substituted
C.sub.3-C.sub.8 ring; and R.sup.15 is selected from hydrogen,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, and aryl.

9. A compound of claim 8, wherein Y is a 1-4 atom spacer comprising at
least one of: an optionally substituted C.sub.1-C.sub.6 alkyl, an
optionally substituted C.sub.1-C.sub.6 heteroalkyl, an optionally
substituted C.sub.2-C.sub.6 alkenyl, and an optionally substituted
C.sub.2-C.sub.6 heteroalkenyl; and at least one of: an optionally
substituted phenyl an optionally substituted heteroaryl, an optionally
substituted C.sub.3-C.sub.5 heterocycle, an optionally substituted
cycloalkyl; and an optionally substituted cycloalkenyl.

16. A compound of claim 13 that is a selective TPO receptor partial
agonist.

17. A compound of claim 13 that is a selective TPO receptor antagonist.

18. A compound of claim 1, 4, or 7 that is a selective TPO receptor
binding compound.

19. The compound of claim 13, wherein the compound is a tissue-specific
modulator.

20. A method for modulating a TPO activity in a cell comprising contacting
a cell with a compound of claim 1, 5, or 9.

21. A method for identifying a compound that modulates a TPO activity,
comprising contacting a cell that expresses a TPO receptor with a
compound of claim 1, 4, or 7; and monitoring an effect of the compound on
the cell.

22. A method of treating patient with a compound of claim 1, 4, or 7.

23. The method of claim 22 wherein the patient suffers form
thrombocytopenia.

24. The method of claim 23 wherein the thrombocytopenia results from
radiation or chemotherapy.

25. The method of claim 22 further comprising harvesting cells from the
patient.

26. The method of claim 22 wherein the treatment is prophylactic.

27. The method of claim 22 wherein the patient suffers from a condition
affecting the nervous system.

28. The method of claim 27 wherein the patient sufferer from a disease
selected from amyotrophic lateral sclerosis, multiple sclerosis, and
multiple dystrophy.

29. The method of claim 27 wherein the patient suffers from injury to the
nervous system.

30. The method of claim 29 wherein the patient suffers from injury to the
spinal cord.

31. A pharmaceutical composition comprising a physiologically acceptable
carrier, diluent, or excipient; and a compound of claim 1, 4, or 7.

32. The pharmaceutical composition of claim 31 for use in treating a
condition selected from thrombocytopenia and a condition affecting the
nervous system.

Description

RELATED APPLICATIONS

[0001] The present application claims priority to the U.S. Provisional
Patent Application Ser. No. 60/621,879, filed on Oct. 25, 2004, by Zhi et
al., and entitled "THROMBOPOIETIN ACTIVITY MODULATING COMPOUNDS AND
METHODS," and the U.S. Provisional Patent Application Ser. No.
60/675,001, filed on Apr. 25, 2005, by Zhi et al., and entitled
"THROMBOPOIETIN ACTIVITY MODULATING COMPOUNDS AND METHODS," both of which
are incorporated by reference herein in their entirety, including any
drawings.

FIELD OF THE INVENTION

[0002] This invention relates to compounds that modulate one or more
thrombopoietin activity and/or bind to thrombopoietin receptors; and to
methods for making and using such compounds.

[0004] In certain instances, TPO activity results from binding of TPO to
the TPO receptor (also called MPL). The TPO receptor has been cloned and
its amino acid sequence has been described. See e.g., Vigon et al., Proc.
Natl. Acad. Sci., 89:5640-5644 (1992).

[0005] In certain instances, TPO modulators may be useful in treating a
variety of hematopoietic conditions, including, but not limited to,
thrombocytopenia. See e.g., Baser et al. Blood 89:3118-3128 (1997);
Fanucchi et al. New Engl. J. Med. 336:404-409 (1997). For example,
patients undergoing certain chemotherapies, including but not limited to
chemotherapy and/or radiation therapy for the treatment of cancer, may
have reduced platelet levels. In certain instances, treating such
patients with a selective TPO modulator increases platelet levels. In
certain instances, selective TPO modulators stimulate production of glial
cells, which may result in repair of damaged nerve cells.

[0006] Certain TPO mimics have been described previously. See e.g., WO
03/103686A1; and WO 01/21180.

[0008] R.sup.1 is selected from CO.sub.2R.sup.10, CONR.sup.10R.sup.11,
SO.sub.3R.sup.10, and a carboxylic acid bioisostere;

[0009] R.sup.2 and R.sup.3 are each independently selected from null,
hydrogen, OR.sup.12, NR.sup.12R.sup.13, an optionally substituted
C.sub.1-C.sub.4 aliphatic, an optionally substituted C.sub.1-C.sub.4
haloaliphatic, an optionally substituted C.sub.1-C.sub.4 heteroaliphatic,
an optionally substituted ring, and (CH.sub.2).sub.mR.sup.14; or R.sup.2
and R.sup.3 taken together form an optionally substituted olefin; or
R.sup.2 and R.sup.3 are linked to form an optionally substituted
C.sub.3-C.sub.8 ring;

[0016] R.sup.12 and R.sup.13 are each independently selected from
hydrogen, an optionally substituted C.sub.1-C.sub.4 aliphatic, an
optionally substituted C.sub.1-C.sub.4 haloaliphatic, an optionally
substituted C.sub.1-C.sub.4 heteroaliphatic, an optionally substituted
ring, and (CH.sub.2).sub.mR.sup.14; or one of R.sup.12 and R.sup.13 is an
optionally substituted C.sub.2-C.sub.6 aliphatic or an optionally
substituted ring and the other of R.sup.12 and R.sup.13 is null; or
R.sup.12 and R.sup.13 are linked to form an optionally substituted
C.sub.3-C.sub.8 ring;

[0017] R.sup.14 is selected from an optionally substituted aryl and an
optionally substituted heteroaryl;

[0018] R.sup.15 is selected from hydrogen, C.sub.1-C.sub.3 aliphatic,
C.sub.1-C.sub.3 haloaliphatic, and a ring;

[0019] Y is a 1-4 atom spacer comprising one or more groups selected from
an optionally substituted C.sub.1-C.sub.6 aliphatic, an optionally
substituted C.sub.1-C.sub.6 heteroaliphatic, an optionally substituted
phenyl, an optionally substituted heteroaryl, an optionally substituted
C.sub.3-C.sub.5 heterocycle, and an optionally substituted alicyclic,

[0020] provided that Y is not --N.dbd.CR.sup.6-- orientated to form a
dihydropyrazole;

[0026] In certain embodiments, the invention provides a compound of
Formula I or a pharmaceutically acceptable salt, ester, amide, or prodrug
thereof, wherein:

[0027] R.sup.1 is selected from CO.sub.2R.sup.10, CONR.sup.10R.sup.11,
SO.sub.3R.sup.10, and a carboxylic acid bioisostere selected from
tetrazole, NHSO.sub.2R.sup.15, OC(S)NR.sup.10R.sup.11,
SC(O)NR.sup.10R.sup.11, and

[0028] wherein A, B, and C are each independently selected from O, S, and
N;

[0029] R.sup.2 and R.sup.3 are each independently selected from hydrogen,
OR.sup.12, NR.sup.12R.sup.13, an optionally substituted C.sub.1-C.sub.4
alkyl, an optionally substituted C.sub.1-C.sub.4 haloalkyl, an optionally
substituted C.sub.1-C.sub.4 heteroalkyl, an optionally substituted ring,
and (CH.sub.2).sub.mR.sup.14; or R.sup.2 and R.sup.3 taken together form
an optionally substituted olefin; or R.sup.2 and R.sup.3 are linked to
form an optionally substituted C.sub.3-C.sub.8 ring;

[0034] R.sup.12 and R.sup.13 are each independently selected from
hydrogen, an optionally substituted C.sub.1-C.sub.4 alkyl, an optionally
substituted C.sub.1-C.sub.4 haloalkyl, an optionally substituted
C.sub.1-C.sub.4 heteroalkyl, an optionally substituted non-aromatic ring,
and (CH.sub.2).sub.mR.sup.14; or one of R.sup.12 and R.sup.13 is an
optionally substituted C.sub.2-C.sub.6 alkyl or an optionally substituted
non-aromatic ring, and the other of R.sup.12 and R.sup.13 is null; or
R.sup.12 and R.sup.13 are linked to form an optionally substituted
C.sub.3-C.sub.8 ring;

[0041] R.sup.1 is selected from CO.sub.2R.sup.10, CONR.sup.10R.sup.11,
SO.sub.3R.sup.10, and a carboxylic acid bioisostere;

[0042] R.sup.2 and R.sup.3 are each independently selected from null,
hydrogen, OR.sup.12, NR.sup.12R.sup.13, an optionally substituted
C.sub.1-C.sub.4 aliphatic, an optionally substituted C.sub.1-C.sub.4
haloaliphatic, an optionally substituted C.sub.1-C.sub.4 heteroaliphatic,
an optionally substituted ring, and (CH.sub.2).sub.mR.sup.14; or R.sup.2
and R.sup.3 taken together form an optionally substituted olefin; or
R.sup.2 and R.sup.3 are linked to form an optionally substituted
C.sub.3-C.sub.8 ring;

[0050] R.sup.12 and R.sup.13 are each independently selected from
hydrogen, an optionally substituted C.sub.1-C.sub.4 aliphatic, an
optionally substituted C.sub.1-C.sub.4 haloaliphatic, an optionally
substituted C.sub.1-C.sub.4 heteroaliphatic, an optionally substituted
ring, and (CH.sub.2).sub.mR.sup.14; or one of R.sup.12 and R.sup.13 is an
optionally substituted C.sub.2-C.sub.6 aliphatic or an optionally
substituted ring and the other of R.sup.12 and R.sup.13 is null; or
R.sup.12 and R.sup.13 are linked to form an optionally substituted
C.sub.3-C.sub.8 ring;

[0051] R.sup.14 is selected from an optionally substituted aryl and an
optionally substituted heteroaryl;

[0052] R.sup.15 is selected from hydrogen, C.sub.1-C.sub.3 aliphatic,
C.sub.1-C.sub.3 haloaliphatic, and a ring;

[0061] In certain embodiments, the invention provides a compound of
Formula II or a pharmaceutically acceptable salt, ester, amide, or
prodrug thereof, wherein:

[0062] R.sup.1 is selected from CO.sub.2R.sup.10, CONR.sup.10R.sup.11,
SO.sub.3R.sup.10, and a carboxylic acid bioisostere selected from
tetrazole, NHSO.sub.2R.sup.15, OC(S)NR.sup.10R.sup.11,
SC(O)NR.sup.10R.sup.11, and

[0063] wherein A, B, and C are each independently selected from O, S, and
N;

[0064] R.sup.2 and R.sup.3 are each independently selected from hydrogen,
OR.sup.12, NR.sup.12R.sup.13, an optionally substituted C.sub.1-C.sub.4
alkyl, an optionally substituted C.sub.1-C.sub.4 haloalkyl, an optionally
substituted C.sub.1-C.sub.4 heteroalkyl, an optionally substituted ring,
and (CH.sub.2).sub.mR.sup.14; or R.sup.2 and R.sup.3 taken together form
an optionally substituted olefin; or R.sup.2 and R.sup.3 are linked to
form an optionally substituted C.sub.3-C.sub.8 ring; or one of R2 or R3
is null and the other is

[0070] R.sup.12 and R.sup.13 are each independently selected from
hydrogen, an optionally substituted C.sub.1-C.sub.4 alkyl, an optionally
substituted C.sub.1-C.sub.4 haloalkyl, an optionally substituted
C.sub.1-C.sub.4 heteroalkyl, an optionally substituted non-aromatic ring,
and (CH.sub.2).sub.mR.sup.14; or one of R.sup.12 and R.sup.13 is an
optionally substituted C.sub.2-C.sub.6 alkyl or an optionally substituted
non-aromatic ring and the other of R.sup.12 and R.sup.13 is null; or
R.sup.12 and R.sup.13 are linked to form an optionally substituted
C.sub.3-C.sub.8 ring;

[0071] R.sup.15 is selected from hydrogen, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl, and aryl; and

[0076] R.sup.1 is selected from CO.sub.2R.sup.10, CONR.sup.10R.sup.11,
SO.sub.3R.sup.10, and a carboxylic acid bioisostere;

[0077] R.sup.2 and R.sup.3 are each independently selected from null,
hydrogen, OR.sup.12, NR.sup.12R.sup.13, an optionally substituted
C.sub.1-C.sub.4 aliphatic, an optionally substituted C.sub.1-C.sub.4
haloaliphatic, an optionally substituted C.sub.1-C.sub.4 heteroaliphatic,
an optionally substituted ring, and (CH.sub.2).sub.mR.sup.14; or R.sup.2
and R.sup.3 taken together form an optionally substituted olefin; or
R.sup.2 and R.sup.3 are linked to form an optionally substituted
C.sub.3-C.sub.8 ring;

[0085] R.sup.12 and R.sup.13 are each independently selected from
hydrogen, an optionally substituted C.sub.1-C.sub.4 aliphatic, an
optionally substituted C.sub.1-C.sub.4 haloaliphatic, an optionally
substituted C.sub.1-C.sub.4 heteroaliphatic, an optionally substituted
ring, and (CH.sub.2).sub.mR.sup.14; or one of R.sup.12 and R.sup.13 is an
optionally substituted C.sub.2-C.sub.6 aliphatic or an optionally
substituted ring and the other of R.sup.12 and R.sup.13 is null; or
R.sup.12 and R.sup.13 are linked to form an optionally substituted
C.sub.3-C.sub.8 ring;

[0086] R.sup.14 is selected from an optionally substituted aryl and an
optionally substituted heteroaryl;

[0087] R.sup.15 is selected from hydrogen, C.sub.1-C.sub.3 aliphatic,
C.sub.1-C.sub.3 haloaliphatic, and a ring;

[0088] m is 0, 1, or 2; and

[0089] n is 0 or 1.

[0090] In certain embodiments, the invention provides a compound of
Formula III or a pharmaceutically acceptable salt, ester, amide, or
prodrug thereof, wherein:

[0091] R.sup.1 is selected from CO.sub.2R.sup.10, CONR.sup.10R.sup.11,
SO.sub.3R.sup.10, and a carboxylic acid bioisostere selected from
tetrazole, NHSO.sub.2R.sup.15, OC(S)NR.sup.10R.sup.11,
SC(O)NR.sup.10R.sup.11, and

[0092] wherein A, B, and C are each independently selected from O, S, and
N;

[0093] R.sup.2 and R.sup.3 are each independently selected from hydrogen,
OR.sup.12, NR.sup.12R.sup.13, an optionally substituted C.sub.1-C.sub.4
alkyl, an optionally substituted C.sub.1-C.sub.4 haloalkyl, an optionally
substituted C.sub.1-C.sub.4 heteroalkyl, an optionally substituted ring,
and (CH.sub.2).sub.mR.sup.14; or R.sup.2 and R.sup.3 taken together form
an optionally substituted olefin; or R.sup.2 and R.sup.3 are linked to
form an optionally substituted C.sub.3-C.sub.8 ring;

[0099] R.sup.12 and R.sup.13 are each independently selected from
hydrogen, an optionally substituted C.sub.1-C.sub.4 alkyl, an optionally
substituted C.sub.1-C.sub.4 haloalkyl, an optionally substituted
C.sub.1-C.sub.4 heteroalkyl, a non-aromatic ring, and
(CH.sub.2).sub.mR.sup.14; or one of R.sup.12 and R.sup.13 is an
optionally substituted C.sub.2-C.sub.6 alkyl or a non-aromatic ring, and
the other of R.sup.12 and R.sup.13 is null; or R.sup.12 and R.sup.13 are
linked to form an optionally substituted C.sub.3-C.sub.8 ring; and

[0103] In certain embodiments, the invention provides methods for
modulating a TPO activity. Certain such methods comprise contacting a
cell with one or more compounds of the present invention. Such methods
include, but are not limited to, contacting TPO and/or a TPO receptor
with one or more compounds of the present invention.

[0104] In certain embodiments, the invention provides a method for
identifying a compound that is capable of modulating TPO activity
comprising contacting a cell capable of a TPO activity with a compound of
the present invention and monitoring an effect on the cell. In certain
such embodiments, the cell expresses a TPO receptor.

[0105] In certain embodiments, the invention provides methods of treating
a patient comprising administering to the patient a compound of the
present invention. In certain embodiments, such a patient suffers from
thrombocytopenia. In certain embodiments, one or more compounds of the
present invention are administered to a patient before, during or after
chemotherapy, bone marrow transplantation, and/or radiation therapy. In
certain embodiments, one or more compounds of the invention are
administered to a patient suffering from aplastic anemia, bone marrow
failure, and/or idiopathic thrombocytopenia. In certain embodiments, one
or more compounds of the present invention are administered to a patient
suffering from a disease of the nervous system. In certain embodiments,
one or more compounds of the present invention are administered to
patient suffering from amyotrophic lateral sclerosis, multiple sclerosis,
or multiple dystrophy. In certain embodiments, one or more compounds of
the present invention are administered to a patient with a nerve injury,
including, but not limited to, a spinal cord injury.

[0106] In certain embodiments, the invention provides pharmaceutical
compositions comprising one or more compounds of the present invention
and a physiologically acceptable carrier, diluent, or excipient.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0107] It is to be understood that both the foregoing general description
and the following detailed description are exemplary and explanatory only
and are not restrictive of the invention claimed. Herein, the use of the
singular includes the plural unless specifically stated otherwise.
Herein, the use of "or" means "and/or" unless stated otherwise.
Furthermore, use of the term "including" as well as other forms, such as
"includes," and "included," is not limiting.

[0108] The section headings used herein are for organizational purposes
only and are not to be construed as limiting the subject matter
described. All documents, or portions of documents, cited in the
application including, but not limited to, patents, patent applications,
articles, books, manuals, and treatises are hereby expressly incorporated
by reference in their entirety for any purpose.

DEFINITIONS

[0109] Unless specific definitions are provided, the nomenclatures
utilized in connection with, and the laboratory procedures and techniques
of, analytical chemistry, synthetic organic chemistry, and medicinal and
pharmaceutical chemistry described herein are those known in the art.
Standard chemical symbols are used interchangeably with the full names
represented by such symbols. Thus, for example, the terms "hydrogen" and
"H" are understood to have identical meaning. Standard techniques may be
used for chemical syntheses, chemical analyses, pharmaceutical
preparation, formulation, and delivery, and treatment of patients.
Standard techniques may be used for recombinant DNA, oligonucleotide
synthesis, and tissue culture and transformation (e.g., electroporation,
lipofection). Reactions and purification techniques may be performed
e.g., using kits according to manufacturer's specifications or as
commonly accomplished in the art or as described herein. The foregoing
techniques and procedures may be generally performed according to
conventional methods well known in the art and as described in various
general and more specific references that are cited and discussed
throughout the present specification. See e.g., Sambrook et al. Molecular
Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory
Press, Cold Spring Harbor, N.Y. (1989)), which is incorporated herein for
any purpose.

[0110] As used herein, the following terms are defined with the following
meanings, unless expressly stated otherwise.

[0111] The term "selective binding compound" refers to a compound that
selectively binds to any portion of one or more target.

[0112] The term "selective TPO receptor binding compound" refers to a
compound that selectively binds to any portion of a TPO receptor.

[0113] The term "selectively binds" refers to the ability of a selective
binding compound to bind to a target receptor with greater affinity than
it binds to a non-target receptor. In certain embodiments, specific
binding refers to binding to a target with an affinity that is at least
10, 50, 100, 250, 500, or 1000 times greater than the affinity for a
non-target.

[0114] The term "target receptor" refers to a receptor or a portion of a
receptor capable of being bound by a selective binding compound. In
certain embodiments, a target receptor is a TPO receptor.

[0115] The term "modulator" refers to a compound that alters or elicits an
activity. For example, the presence of a modulator may result in an
increase or decrease in the magnitude of a certain activity compared to
the magnitude of the activity in the absence of the modulator. In certain
embodiments, a modulator is an inhibitor, which decreases the magnitude
of one or more activities. In certain embodiments, an inhibitor
completely prevents one or more biological activities. In certain
embodiments, a modulator is an activator, which increases the magnitude
of at least one activity. In certain embodiments the presence of a
modulator results in a activity that does not occur in the absence of the
modulator.

[0116] The term "selective modulator" refers to a compound that
selectively modulates a target activity.

[0117] The term "selective TPO modulator" refers to a compound that
selectively modulates at least one TPO activity. The term selective TPO
modulator includes, but is not limited to "TPO mimic" which refers to a
compound, the presence of which results in at least one TPO activity.

[0118] The term "selectively modulates" refers to the ability of a
selective modulator to modulate a target activity to a greater extent
than it modulates a non-target activity.

[0119] The term "target activity" refers to a biological activity capable
of being modulated by a selective modulator. Certain exemplary target
activities include, but are not limited to, binding affinity; signal
transduction; enzymatic activity; transcription of one or more genes; the
proliferation and/or differentiation of cells, including, but not limited
to progenitor cells; generation of platelets; and alleviation of symptoms
of a disease or condition.

[0120] The term "TPO activity" refers to a biological activity that
results, either directly or indirectly from the presence of TPO.
Exemplary TPO activities include, but are not limited to, proliferation
and or differentiation of progenitor cells to produce platelets;
hematopoiesis; growth and/or development of glial cells; repair of nerve
cells; and alleviation of thrombocytopenia.

[0121] The term "thrombocytopenia" refers to a condition wherein the
concentration of platelets in the blood of a patient is below what is
considered normal for a healthy patient. In certain embodiments,
thrombocytopenia is a platelet count less than 450,000, 400,000, 350,000,
300,000, 250,000, 200,000, 150,000, 140,000, 130,000, 120,000, 110,000,
100,000, 75,000, or 50,000 platelets per microliter of blood.

[0122] The term "receptor mediated activity" refers any biological
activity that results, either directly or indirectly, from binding of a
ligand to a receptor.

[0123] The term "agonist" refers to a compound, the presence of which
results in a biological activity of a receptor that is the same as the
biological activity resulting from the presence of a naturally occurring
ligand for the receptor.

[0124] The term "partial agonist" refers to a compound, the presence of
which results in a biological activity of a receptor that is of the same
type as that resulting from the presence of a naturally occurring ligand
for the receptor, but of a lower magnitude.

[0125] The term "antagonist" refers to a compound, the presence of which
results in a decrease in the magnitude of a biological activity of a
receptor. In certain embodiments, the presence of an antagonist results
in complete inhibition of a biological activity of a receptor.

[0126] The term "aliphatic," alone or in combination, refers to a straight
or branched chain comprising at least one carbon atom. Aliphatics include
alkyls, alkenyls, and alkynyls. In certain embodiments, aliphatics are
optionally substituted. Aliphatics include, but are not limited to,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl,
pentyl, hexyl, ethenyl, propenyl, butenyl, ethynyl, butynyl, propynyl,
and the like, each of which may be optionally substituted. As used
herein, aliphatic is not intended to include cyclic groups.

[0127] The term "alkyl," alone or in combination, refers to a fully
saturated aliphatic. In certain embodiments, alkyls are optionally
substituted. In certain embodiments, an alkyl comprises 1 to 20 carbon
atoms (whenever it appears herein, a numerical range, such as "1 to 20"
or "C.sub.1-C.sub.20", refers to each integer in the given range; e.g.,
"C.sub.1-C.sub.20 alkyl" means that an alkyl group comprising only 1
carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20
carbon atoms). Examples of alkyls include, but are not limited to,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like.

[0128] The term "alkenyl," alone or in combination, refers to an aliphatic
having one or more carbon-carbon double-bonds. In certain embodiments,
alkenyls are optionally substituted. Examples of alkenyls include, but
are not limited to, ethenyl, propenyl, 1,4-butadienyl, and the like.

[0129] The term "alkynyl," alone or in combination, refers to an aliphatic
having one or more carbon-carbon triple-bonds. In certain embodiments,
alkynyls are optionally substituted. Examples of alkynyls include, but
are not limited to, ethynyl, propynyl, butynyl, and the like.

[0130] The term "haloaliphatic," alone or in combination, refers to an
aliphatic in which at least one hydrogen atom is replaced with a halogen
atom. In certain embodiments in which two or more hydrogen atom are
replaced with halogen atoms, the halogen atoms are all the same as one
another. In certain such embodiments, the halogen atoms are not all the
same as one another. Haloaliphatics include haloalkyls, haloalkenyls, and
haloalkynyls. In certain embodiments, haloaliphatics are optionally
substituted, in addition to the hydrogen/halogen substitution. The term
"haloaliphatic" also includes perhaloaliphatic, in which all of the
hydrogen atoms of the aliphatic are replaced by halogen atoms. Examples
of perhaloaliphatic include trichloromethyl, pentacholorethyl, etc.

[0131] The term "heteroaliphatic," alone or in combination, refers to a
group comprising an aliphatic and one or more heteroatoms. Certain
heteroaliphatics are acylaliphatics, in which the one or more heteroatoms
is not within an aliphatic chain. Heteroaliphatics include heteroalkyls,
including, but not limited to acylalkys; heteroalkenyls, including, but
not limited to, acylalkenyls; and heteroalkynyls, including, but not
limited acylalkynyls. Examples of heteraliphatics include, but are not
limited to, CH.sub.3C(.dbd.O)CH.sub.2--,
CH.sub.3C(.dbd.O)CH.sub.2CH.sub.2--,
CH.sub.3CH.sub.2C(.dbd.O)CH.sub.2CH.sub.2--,
CH.sub.3C(.dbd.O)CH.sub.2CH.sub.2CH.sub.2--, CH.sub.3OCH.sub.2CH.sub.2--,
CH.sub.3NHCH.sub.2--, and the like. In certain embodiments,
heteroaliphatics are optionally substituted.

[0132] The term "heterohaloaliphatic" refers to a heteroaliphatic in which
at least one hydrogen atom is replaced with a halogen atom.
Heterohaloaliphatics include heterohaloalkyls, heterohaloalkenyls, and
heterohaloalkynyls. In certain embodiments, heterohaloaliphatics are
optionally substituted.

[0133] The term "olefin" refers to a C.dbd.C bond. The term "together form
an olefin" refers to instances where two groups are bound to the same
carbon atom and one of those two groups is .dbd.C and the other of those
two groups is null. For example, if R' and R'' in the structure below
together form an olefin: the resulting structure is:

[0134] wherein R''' and R'''' represent hydrogen. Olefins may be optional
substituted, in which case R''' and R'''' above are independently
selected from hydrogen and an optional substituent.

[0135] The term "carbocycle" refers to a group comprising a covalently
closed ring, wherein each of the atoms forming the ring is a carbon atom.
Carbocylic rings may be formed by three, four, five, six, seven, eight,
nine, or more than nine carbon atoms. Carbocycles may be optionally
substituted.

[0136] The term "heterocycle" refers to a group comprising a covalently
closed ring wherein at least one atom forming the ring is a carbon atom
and at least one atom forming the ring is a heteroatom. Heterocyclic
rings may be formed by three, four, five, six, seven, eight, nine, or
more than nine atoms. Any number of those atoms may be heteroatoms (i.e.,
a heterocyclic ring may comprise one, two, three, four, five, six, seven,
eight, nine, or more than nine heteroatoms). Herein, whenever the number
of carbon atoms in a heterocycle is indicated (e.g., C.sub.1-C.sub.6
heterocycle), at least one other atom (the heteroatom) must be present in
the ring. Designations such as "C.sub.1-C.sub.6 heterocycle" refer only
to the number of carbon atoms in the ring and do not refer to the total
number of atoms in the ring. It is understood that the heterocylic ring
will have additional heteroatoms in the ring. In heterocycles comprising
two or more heteroatoms, those two or more heteroatoms may be the same or
different from one another. Heterocycles may be optionally substituted.
Binding to a heterocycle can be at a heteroatom or via a carbon atom.
Examples of heterocycles include, but are not limited to the following:
wherein D, E, F, and G independently represent a heteroatom. Each of D,
E, F, and G may be the same or different from one another.

[0137] The term "heteroatom" refers to an atom other than carbon or
hydrogen. Heteroatoms are typically independently selected from oxygen,
sulfur, nitrogen, and phosphorus, but are not limited to those atoms. In
embodiments in which two or more heteroatoms are present, the two or more
heteroatoms may all be the same as one another, or some or all of the two
or more heteroatoms may each be different from the others.

[0138] The term "aromatic" refers to a group comprising a covalently
closed planar ring having a delocalized .pi.-electron system comprising
4n+2.pi. electrons, where n is an integer. Aromatic rings may be formed
by five, six, seven, eight, nine, or more than nine atoms. Aromatics may
be optionally substituted. Examples of aromatic groups include, but are
not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl,
tetralinyl, fluorenyl, indenyl, and indanyl. The term aromatic includes,
for example, benzenoid groups, connected via one of the ring-forming
carbon atoms, and optionally carrying one or more substituents selected
from an aryl, a heteroaryl, a cycloalkyl, a non-aromatic heterocycle, a
halo, a hydroxy, an amino, a cyano, a nitro, an alkylamido, an acyl, a
C.sub.1-6 alkoxy, a C.sub.1-6 alkyl, a C.sub.1-6 hydroxyalkyl, a
C.sub.1-6 aminoalkyl, a C.sub.1-6 alkylamino, an alkylsulfinyl, an
alkylsulfinyl, an alkylsulfonyl, an sulfamoyl, or a trifluoromethyl. In
certain embodiments, an aromatic group is substituted at one or more of
the para, meta, and/or ortho positions. Examples of aromatic groups
comprising substitutions include, but are not limited to, phenyl,
3-halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,
3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl,
3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl,
hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl,
4-morpholin-4-ylphenyl, 4-pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl,
4-triazolylphenyl, and 4-(2-oxopyrrolidin-1-yl)phenyl.

[0139] The term "aryl" refers to an aromatic ring wherein each of the
atoms forming the ring is a carbon atom. Aryl rings may be formed by
five, six, seven, eight, nine, or more than nine carbon atoms. Aryl
groups may be optionally substituted.

[0140] The term "heteroaryl" refers to an aromatic heterocycle. Heteroaryl
rings may be formed by three, four, five, six, seven, eight, nine, or
more than nine atoms. Heteroaryls may be optionally substituted. Examples
of heteroaryl groups include, but are not limited to, aromatic C.sub.3-8
heterocyclic groups comprising one oxygen or sulfur atom or up to four
nitrogen atoms, or a combination of one oxygen or sulfur atom and up to
two nitrogen atoms, and their substituted as well as benzo- and
pyrido-fused derivatives, for example, connected via one of the
ring-forming carbon atoms. In certain embodiments, heteroaryl groups are
optionally substituted with one or more substituents, independently
selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl,
C.sub.1-6-alkoxy, C.sub.1-6-alkyl, C.sub.1-6-hydroxyalkyl,
C.sub.1-6-aminoalkyl, C.sub.1-6-alkylamino, alkylsulfenyl, alkylsulfinyl,
alkylsulfonyl, sulfamoyl, or trifluoromethyl. Examples of heteroaryl
groups include, but are not limited to, unsubstituted and mono- or
di-substituted derivatives of furan, benzofuran, thiophene,
benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole,
isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole,
imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline,
isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan,
1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole,
benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole,
quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In
some embodiments, the substituents are halo, hydroxy, cyano,
O--C.sub.1-6-alkyl, C.sub.1-6-alkyl, hydroxy-C.sub.1-6-alkyl, and
amino-C.sub.1-6-alkyl.

[0141] The term "non-aromatic ring" refers to a group comprising a
covalently closed ring that is not aromatic.

[0142] The term "alicyclic" refers to a group comprising a non-aromatic
ring wherein each of the atoms forming the ring is a carbon atom.
Alicyclic rings may be formed by three, four, five, six, seven, eight,
nine, or more than nine carbon atoms. In certain embodiments, alicyclics
are optionally substituted. In certain embodiments, an alicyclic
comprises one or more unsaturated bonds. Alicyclics include cycloalkyls,
cycloalkenyls, and cycloalkynyls. Examples of alicyclics include, but are
not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene,
cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene,
1,4-cyclohexadiene, cycloheptane, and cycloheptene. In certain
embodiments, alicylcic rings are optionally substituted.

[0144] The term "arylalkyl" refers to a group comprising an aryl group
bound to an alkyl group.

[0145] The term "ring" refers to any covalently closed structure. Rings
include, for example, carbocycles (e.g., aryls and alicyclics),
heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics
(e.g., aryls and heteroaryls), and non-aromatics (e.g., alicyclics and
non-aromatic heterocycles). Rings may be optionally substituted. Rings
may form part of a ring system.

[0146] The term "ring system" refers to two or more rings, wherein two or
more of the rings are fused. The term "fused" refers to structures in
which two or more rings share one or more bonds.

[0147] The term "null" refers to a group being absent from a structure.
For example, in the structure where in certain instances X is N, if X
is N, one of R' or R'' is null, meaning that only three groups are bound
to the N.

[0148] The term "carboxylic acid bioisostere" refers to a group that is
biologically equivalent to a carboxylic acid. For example, carboxylic
acid bioisosteres include, but are not limited to, tetrazole,
NHSO.sub.2R.sup.15, OC(S)NR.sup.10R.sup.11, SC(O)NR.sup.10R.sup.11,
thiazolidinedione, oxazolidinedione, and 1-oxa-2,4-diazolidine-3,5-dione.
In certain embodiments, a carboxylic acid bioisoster comprises the
following structure: wherein A, B, and C are each independently
selected from O, S, and N.

[0149] The term "spacer" refers to an atom or group of atoms that separate
two or more groups from one another by a desired number of atoms. For
example, in certain embodiments, it may be desirable to separate two or
more groups by one, two, three, four, five, six, or more than six atoms.
In such embodiments, any atom or group of atoms may be used to separate
those groups by the desired number of atoms. In certain embodiments,
spacers are optionally substituted. In certain embodiments, a spacer
comprises an aliphatic. In certain embodiments, a spacer comprises atoms
that are part of a ring.

[0150] Solely for the purposes of illustration, and without limiting the
above definition, some examples of spacers are provided. Examples of
1-atom spacers include, but are not limited to, the following: where A
and B represent groups which are separated by the desired number of
atoms. Examples of 2-atom spacers include, but are not limited to, the
following: where A and B represent groups which are separated by the
desired number of atoms. Examples of 3-atom spacers include, but are not
limited to, the following: where A and B represent groups that are
separated by the desired number of atoms.

[0151] In certain embodiments, a spacer separates atoms in a ring. For
example, in the structure: where Q is a 1-atom spacer, the resulting
ring is a three-membered ring comprising A, B, and Q, where Q may be
optionally substituted. An example of such a structure includes, but is
not limited to: If Q is a 2-atom spacer, then a four-membered ring
results; if Q is a three atom spacer, then a five-membered ring results;
if Q is a four atom spacer, then a six-membered ring results; if Q is a
five atom spacer, then a seven-membered ring results; if Q is a six atom
spacer, then an eight-membered ring results; and so on. In certain
embodiments, a spacer in a ring comprises a ring, such that the ring
formed by the spacer and the ring comprised by the spacer are fused. For
example, referring to the structure above where Q is a 3-atom spacer
comprising a fused ring includes, but is not limited to, structures such
as: where the fused ring can be fused at any bond of the spacer. Such a
fused ring may be optionally substituted and may be heterocyclic or
carbocyclic.

[0152] As is evident from the above examples, the atoms of a spacer that
create the desired separation may themselves be part of a group. That
group may be, for example, an aliphatic, heteroaliphatic, haloaliphatic,
heterohaloaliphatic, alicyclic, aryl, arylalkyl, heteroaryl, non-aromatic
heterocycle, or substituted alkyl all of which are optionally
substituted. Thus, the term "1-5 atom spacer" refers to a spacer that
separates two groups by 1, 2, 3, 4, or 5 atoms and does not indicate the
total size of the group that constitutes the spacer.

[0153] The term "linked to form a ring" refers to the circumstance where
two atoms that are bound either to a single atom or to atoms that are
themselves ultimately bound, are each bound to a linking group, such that
the resulting structure forms a ring. That resulting ring comprises the
two atoms, the atom (or atoms) that previously linked those atoms, and
the linker. For example, if A and B below are "linked to form a ring"
the resulting ring includes A, B, the carbon atom to which both A and B
are bound, and a linking group. Unless otherwise indicated, that linking
group may be of any length and may be optionally substituted. Referring
to the above example, resulting structures include, but are not limited
to: and the like. In certain embodiments, the two atoms that are linked
to form a ring are not bound to the same atom. For example, if A and B,
below, are linked to form a ring: the resulting ring comprises A, B,
the 3 carbon atoms that already link A and B, and a linking group.
Examples of resulting structures include, but are not limited to: and
the like.

[0154] The substituent "R" appearing by itself and without a number
designation refers to a substituent selected from alkyl, cycloalkyl,
aryl, heteroaryl (bonded through a ring carbon) and non-aromatic
heterocycle (bonded through a ring carbon).

[0155] The term "O-carboxy" refers to a group of formula RC(.dbd.O)O--.

[0156] The term "C-carboxy" refers to a group of formula --C(.dbd.O)OR.

[0157] The term "acetyl" refers to a group of formula --C(.dbd.O)CH.sub.3.

[0158] The term "trihalomethanesulfonyl" refers to a group of formula
X.sub.3CS(.dbd.O).sub.2-- where X is a halogen.

[0159] The term "cyano" refers to a group of formula --CN.

[0160] The term "isocyanato" refers to a group of formula --NCO.

[0161] The term "thiocyanato" refers to a group of formula --CNS.

[0162] The term "isothiocyanato" refers to a group of formula --NCS.

[0163] The term "sulfonyl" refers to a group of formula --S(.dbd.O)--R.

[0164] The term "S-sulfonamido" refers to a group of formula
--S(.dbd.O).sub.2NR.

[0165] The term "N-sulfonamido" refers to a group of formula
RS(.dbd.O).sub.2NH--.

[0166] The term "trihalomethanesulfonamido" refers to a group of formula
X.sub.3CS(.dbd.O).sub.2NR--.

[0167] The term "O-carbamyl" refers to a group of formula
--OC(.dbd.O)--NR.

[0168] The term "N-carbamyl" refers to a group of formula ROC(.dbd.O)NH--.

[0169] The term "O-thiocarbamyl" refers to a group of formula
--OC(.dbd.S)--NR.

[0170] The term "N-thiocarbamyl" refers to a group of formula
ROC(.dbd.S)NH--.

[0171] The term "C-amido" refers to a group of formula
--C(.dbd.O)--NR.sub.2.

[0172] The term "N-amido" refers to a group of formula RC(.dbd.O)NH--.

[0173] The term "ester" refers to a chemical moiety with formula
--(R).sub.n--COOR', where R and R' are independently selected from alkyl,
cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and
non-aromatic heterocycle (bonded through a ring carbon), where n is 0 or
1.

[0174] The term "amide" refers to a chemical moiety with formula
--(R).sub.n--C(O)NHR' or --(R).sub.n--NHC(O)R', where R and R' are
independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded
through a ring carbon) and heteroalicyclic (bonded through a ring
carbon), where n is 0 or 1. In certain embodiments, an amide may be an
amino acid or a peptide.

[0175] The terms "amine," "hydroxy," and "carboxyl" include such groups
that have been esterified or amidified. Procedures and specific groups
used to achieve esterification and amidification are known to those of
skill in the art and can readily be found in reference sources such as
Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd Ed.,
John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein in
its entirety.

[0176] Unless otherwise indicated, the term "optionally substituted,"
refers to a group in which none, one, or more than one of the hydrogen
atoms has been replaced with one or more group(s) are independently
selected from: alkyl, heteroalkyl, haloalkyl, heteroholoalkyl,
cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle,
hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo,
carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,
C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro,
silyl, trihalomethanesulfonyl, and amino, including mono- and
di-substituted amino groups, and the protected derivatives of amino
groups. Such protective derivatives (and protecting groups that may form
such protective derivatives) are known to those of skill in the art and
may be found in references such as Greene and Wuts, above. In embodiments
in which two or more hydrogen atoms have been substituted, the
substituent groups may be linked to form a ring.

[0177] The term "carrier" refers to a compound that facilitates the
incorporation of another compound into cells or tissues. For example,
dimethyl sulfoxide (DMSO) is a commonly used carrier for improving
incorporation of certain organic compounds into cells or tissues.

[0178] The term "pharmaceutical agent" refers to a chemical compound or
composition capable of inducing a desired therapeutic effect in a
patient. In certain embodiments, a pharmaceutical agent comprises an
active agent, which is the agent that induces the desired therapeutic
effect. In certain embodiments, a pharmaceutical agent comprises a
prodrug. In certain embodiments, a pharmaceutical agent comprises
inactive ingredients such as carriers, excipients, and the like.

[0179] The term "pharmaceutical composition" refers to a pharmaceutical
agent together with one or more inactive ingredient for pharmaceutical
administration, such as a carrier, excipient, or the like.

[0180] The term "therapeutically effective amount" refers to an amount of
a pharmaceutical agent or composition sufficient to achieve a desired
therapeutic effect.

[0181] The term "prodrug" refers to an pharmaceutical agent that is
converted from a less active form into a corresponding more active form
in vivo.

[0182] The term "pharmaceutically acceptable" refers to a formulation of a
compound that does not significantly abrogate the biological activity, a
pharmacological activity and/or other properties of the compound when the
formulated compound is administered to a patient. In certain embodiments,
a pharmaceutically acceptable formulation does not cause significant
irritation to a patient.

[0183] The term "co-administer" refers to administering more than one
pharmaceutical agent to a patient. In certain embodiments,
co-administered pharmaceutical agents are administered together in a
single dosage unit. In certain embodiments, co-administered
pharmaceutical agents are administered separately. In certain
embodiments, co-administered pharmaceutical agents are administered at
the same time. In certain embodiments, co-administered pharmaceutical
agents are administered at different times.

[0184] The term "patient" includes human and animal subjects.

[0185] The term "substantially pure" means an object species (e.g.
compound) is the predominant species present (i.e., on a molar basis it
is more abundant than any other individual species in the composition).
In certain embodiments, a substantially purified fraction is a
composition wherein the object species comprises at least about 50
percent (on a molar basis) of all species present. In certain
embodiments, a substantially pure composition will comprise more than
about 80%, 85%, 90%, 95%, or 99% of all species present in the
composition. In certain embodiments, the object species is purified to
essential homogeneity (contaminant species cannot be detected in the
composition by conventional detection methods) wherein the composition
consists essentially of a single species.

[0186] The term "tissue-selective" refers to the ability of a compound to
modulate a biological activity in one tissue to a greater or lesser
degree than it modulates a biological activity in another tissue. The
biological activities in the different tissues may be the same or they
may be different. The biological activities in the different tissues may
be mediated by the same type of target receptor. For example, in certain
embodiments, a tissue-selective compound may modulate receptor mediated
biological activity in one tissue and fail to modulate, or modulate to a
lesser degree, receptor mediated biological activity in another tissue
type.

[0187] The term "monitoring" refers to observing an effect or absence of
any effect. In certain embodiments, one monitors cells after contacting
those cells with a compound of the present invention. Examples of effects
that may be monitored include, but are not limited to, changes in cell
phenotype, cell proliferation, receptor activity, or the interaction
between a receptor and a compound known to bind to the receptor.

[0188] The term "cell phenotype" refers to physical or biological
characteristics of a cell. Examples of characteristics that constitute
phenotype included, but are not limited to, cell size, cell
proliferation, cell differentiation, cell survival, apoptosis (cell
death), or the utilization of a metabolic nutrient (e.g., glucose
uptake). Certain changes or the absence of changes in cell phenotype are
readily monitored using techniques known in the art.

[0189] The term "cell proliferation" refers to the rate at which cells
divide. In certain embodiments, cells are in situ in an organism. In
certain embodiments, cell are grown in vitro in a vessel. The number of
cells growing in a vessel can be quantified by a person skilled in the
art (e.g., by counting cells in a defined area using a microscope or by
using laboratory apparatus that measure the density of cells in an
appropriate medium). One skilled in that art can calculate cell
proliferation by determining the number of cells at two or more times.

[0190] The term "contacting" refers to bringing two or more materials into
close enough proximity that they may interact. In certain embodiments,
contacting can be accomplished in a vessel such as a test tube, a petri
dish, or the like. In certain embodiments, contacting may be performed in
the presence of additional materials. In certain embodiments, contacting
may be performed in the presence of cells. In certain of such
embodiments, one or more of the materials that are being contacted may be
inside a cell. Cells may be alive or may dead. Cells may or may not be
intact.

Certain Compounds

[0191] Certain compounds that modulate one or more TPO activity and/or
bind to TPO receptors play a role in health. In certain embodiments,
compounds of the present invention are useful for treating any of a
variety of diseases or conditions.

[0193] In certain embodiments, the present invention relates to compounds
of Formula I, II, or III: or a pharmaceutically acceptable salt, ester,
amide, or prodrug thereof.

[0194] In certain embodiments, R.sup.1 is selected from hydrogen,
CO.sub.2R.sup.10, CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a carboxylic
acid bioisostere. In certain embodiments in which R.sup.1 is a carboxylic
acid bioisostere, R.sup.1 is selected from tetrazole, NHSO.sub.2R.sup.15,
OC(S)NR.sup.10R.sup.11, SC(O)NR.sup.10R.sup.11, thiazolidinedione,
oxazolidinedione, and 1-oxa-2,4-diazolidine-3,5-dione.

[0195] In certain embodiments, R.sup.2 and R.sup.3 are each independently
selected from hydrogen, OR.sup.12, NR.sup.12R.sup.13, an optionally
substituted C.sub.1-C.sub.4 aliphatic, an optionally substituted
C.sub.1-C.sub.4 haloaliphatic, an optionally substituted C.sub.1-C.sub.4
heteroaliphatic, (CH.sub.2).sub.mR.sup.14, an optionally substituted
ring, and null. In certain such embodiments, R.sup.2 and R.sup.3 are each
independently selected from an optionally substituted C.sub.1-C.sub.4
alkyl, an optionally substituted C.sub.1-C.sub.4 haloalkyl, an optionally
substituted C.sub.1-C.sub.4 heteroalkyl. In certain embodiments, R.sup.2
and R.sup.3 taken together form an optionally substituted olefin. In
certain embodiments, R.sup.2 and R.sup.3 are linked to form an optionally
substituted C.sub.3-C.sub.8 ring. In certain such embodiments, R.sup.2
and R.sup.3 are linked to form an optionally substituted carbocycle, an
optionally substituted heterocycle, an optionally substituted aromatic,
or an optionally substituted non-aromatic ring. In certain such
embodiments, R.sup.2 and R.sup.3 are linked to form an optionally
substituted aryl, an optionally substituted heteroaryl, an optionally
substituted alicyclic, or an optionally substituted non-aromatic
heterocyclic. In certain embodiments, R.sup.2 and R.sup.3 are linked to
form an optionally substituted aryl or an optionally substituted
heteroaryl. In certain embodiments, R.sup.2 and R.sup.3 are linked to
form an optionally substituted aryl. In certain embodiments, R.sup.2 and
R.sup.3 are linked to form an aryl.

[0199] In certain embodiments, R.sup.7 is selected from hydrogen, an
optionally substituted C.sub.1-C.sub.8 aliphatic, an optionally
substituted C.sub.1-C.sub.8 haloaliphatic, an optionally substituted
C.sub.1-C.sub.8 heteroaliphatic, an optionally substituted
C.sub.1-C.sub.8 heterohaloaliphatic, an optionally substituted ring, and
(CH.sub.2).sub.mR.sup.14. In certain such embodiments, R.sup.7 is
selected from an optionally substituted C.sub.1-C.sub.8 alkyl, an
optionally substituted C.sub.1-C.sub.8 haloalkyl, an optionally
substituted C.sub.1-C.sub.8 heteroalkyl, and an optionally substituted
C.sub.1-C.sub.8 heterohaloalkyl. In certain embodiments, R.sup.7 is
selected from an optionally substituted carbocycle, an optionally
substituted heterocycle, and optionally substituted aromatic, and an
optionally substituted non-aromatic ring. In certain such embodiments,
R.sup.7 is selected from an optionally substituted aryl, an optionally
substituted heteroaryl, an optionally substituted alicyclic, and an
optionally substituted non-aromatic heterocyclic. In certain embodiments,
R.sup.7 is selected from an optionally substituted aryl and an optionally
substituted heteroaryl. In certain embodiments, R.sup.7 is selected from
an optionally substituted aryl. In certain such embodiments, R.sup.7 is
selected from an aryl ring optionally fused to one or more additional
rings. In certain embodiments, R.sup.7 is an aryl. In certain
embodiments, R.sup.7 is an optionally substituted phenyl ring.

[0203] In some embodiments, R.sup.12 and R.sup.13 are each independently
selected from hydrogen, optionally substituted C.sub.1-C.sub.4 aliphatic,
optionally substituted C.sub.1-C.sub.4 haloaliphatic, optionally
substituted C.sub.1-C.sub.4 heteroaliphatic, optionally substituted
C.sub.1-C.sub.4 heterohaloaliphatic, an optionally substituted ring, and
(CH.sub.2).sub.mR.sup.14. In certain such embodiments, R.sup.12 and/or
R.sup.13 is independently selected from optionally substituted
C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.1-C.sub.4 haloalkyl,
optionally substituted C.sub.1-C.sub.4 heteroalkyl, and optionally
substituted C.sub.1-C.sub.4 heterohaloalkyl. In certain embodiments,
R.sup.12 and/or R.sup.13 is selected from an optionally substituted
carbocycle, an optionally substituted heterocycle, and optionally
substituted aromatic, and an optionally substituted non-aromatic ring. In
certain such embodiments, R.sup.12 and/or R.sup.13 is selected from an
optionally substituted aryl, an optionally substituted heteroaryl, an
optionally substituted alicyclic, and an optionally substituted
non-aromatic heterocyclic. In certain embodiments, R.sup.12 and/or
R.sup.13 is selected from an optionally substituted aryl and an
optionally substituted heteroaryl. In certain embodiments, R.sup.12
and/or R.sup.13 is selected from an optionally substituted aryl. In
certain embodiments, R.sup.12 and/or R.sup.13 is an aryl. In certain
embodiments, one of R.sup.12 or R.sup.13 is a ring and the other of
R.sup.12 and R.sup.13 is hydrogen.

[0204] In certain embodiments, R.sup.12 and R.sup.13 are linked to form an
optionally substituted C.sub.2-C.sub.8 heterocycle. In certain
embodiments, R.sup.12 and R.sup.13 are linked to form an optionally
substituted C.sub.2-C.sub.8 heteroaryl. In certain embodiments, R.sup.12
and R.sup.13 are linked to form an optionally substituted C.sub.2-C.sub.8
non-aromatic heterocycle.

[0205] In certain embodiments, R.sup.14 is selected from an optionally
substituted ring. In certain such embodiments, R.sup.14 is selected from
an optionally substituted carbocycle, an optionally substituted
heterocycle, and optionally substituted aromatic, and an optionally
substituted non-aromatic ring. In certain such embodiments, R.sup.14 is
selected from an optionally substituted aryl, an optionally substituted
heteroaryl, an optionally substituted alicyclic, and an optionally
substituted non-aromatic heterocyclic. In certain embodiments, R.sup.14
is selected from an optionally substituted aryl and an optionally
substituted heteroaryl. In certain embodiments, R.sup.14 is selected from
an optionally substituted aryl. In certain embodiments, R.sup.14 is an
aryl.

[0206] In certain embodiments, R.sup.15 is selected from hydrogen,
optionally substituted C.sub.1-C.sub.3 aliphatic, optionally substituted
C.sub.1-C.sub.3 haloaliphatic, and optionally substituted ring. In
certain such embodiments, R.sup.15 is selected from optionally
substituted C.sub.1-C.sub.3 alkyl, and optionally substituted
C.sub.1-C.sub.3 haloalkyl. In certain embodiments, R.sup.15 is an
optionally substituted aryl. In certain embodiments, R.sup.15 is selected
from an alkyl, a haloalkyl, an alicyclic, and an aryl. In certain
embodiments, R.sup.15 is selected from an optionally substituted ring. In
certain such embodiments, R.sup.15 is selected from an optionally
substituted carbocycle, an optionally substituted heterocycle, and
optionally substituted aromatic, and an optionally substituted
non-aromatic ring. In certain such embodiments, R.sup.15 is selected from
an optionally substituted aryl, an optionally substituted heteroaryl, an
optionally substituted alicyclic, and an optionally substituted
non-aromatic heterocyclic. In certain embodiments, R.sup.15 is selected
from an optionally substituted aryl and an optionally substituted
heteroaryl. In certain embodiments, R.sup.15 is selected from an
optionally substituted aryl. In certain embodiments, R.sup.15 is an aryl.

[0216] In certain embodiments, n is 0 or 1. In embodiments in which n is
0, R.sup.1 binds directly to Z and R.sup.2 and/or R.sup.3 are null, as
appropriate. For example, if Z is a phenyl ring and n is 0, then R.sup.1
binds directly to the phenyl ring and both R.sup.1 and R.sup.2 are null.

[0217] In embodiments in which two or more of a particular group are
present, the identities of those two or more particular groups are
selected independently and, thus, may be the same or different from one
another. For example, certain compounds of the invention comprise two or
more R.sup.14 groups. The identities of those two or more R.sup.14 groups
are each selected independently. Thus, in certain embodiments, those
R.sup.14 groups are all the same as one another; in certain embodiments,
those R.sup.14 groups are all different from one another; and in certain
embodiments, some of those R.sup.14 groups are the same as one another
and some are different from one another. This independent selection
applies to any group that is present in a compound more than once.

[0218] One of ordinary skill in the art will recognize that the complete
lists of possible identities for each above-listed group (all R groups,
Y, Q, Z, m, and n) may be narrowed to provide shorter lists of possible
identities. For example, since in certain embodiments R.sup.1 is selected
from hydrogen, CO.sub.2R.sup.10, CONR.sup.10R.sup.11, SO.sub.3R.sup.10,
and a carboxylic acid bioisostere, it is to be understood that in certain
embodiments, R.sup.1 may be selected from CO.sub.2R.sup.10,
CONR.sup.10R.sup.11, and SO.sub.3R.sup.10, because each of those possible
identities is included on the longer list of possible identities. One of
ordinary skill in the art will also recognize that broader terms include
combinations of narrower terms, which may be substituted and selected.
For example, in certain embodiments, R.sup.2 is selected from an
optionally substituted C.sub.1-C.sub.4 aliphatic. Because aliphatics
include, but are not limited to, alkyls and alkenes, in certain
embodiments, R.sup.2 may be selected from an optionally substituted
C.sub.1-C.sub.4 alkyl and an optionally substituted C.sub.1-C.sub.4
alkenyl. Similarly, in certain embodiments, R.sup.2 is selected from an
optionally substituted C.sub.2-C.sub.3 alkyl and an optionally
substituted C.sub.2-C.sub.4 alkenyl, because those alkyls and alkenyls
are included in the definition of C.sub.1-C.sub.4 aliphatics.

[0219] One of ordinary skill in the art will also understand that the
above listed groups may be selected in any combination. For example, in
certain embodiments, R.sup.1 is selected from hydrogen, CO.sub.2R.sup.10,
CONR.sup.10R.sup.11, SO.sub.3R.sup.10, and a carboxylic acid bioisostere;
and R.sup.2 is selected from hydrogen, OR.sup.12, NR.sup.12R.sup.13, an
optionally substituted C.sub.1-C.sub.4 aliphatic, an optionally
substituted C.sub.1-C.sub.4 haloaliphatic, an optionally substituted
C.sub.1-C.sub.4 heteroaliphatic, (CH.sub.2).sub.mR.sup.14, an optionally
substituted ring, and null. Therefore, in certain embodiments, R.sup.1
may be selected from hydrogen, and CO.sub.2R.sup.10; and at the same time
R.sup.2 may be selected from hydrogen, OR.sup.12, NR.sup.12R.sup.13, and
an optionally substituted C.sub.1-C.sub.4 aliphatic, because those lists
of possible identities are included within the previous lists of possible
identities. Such selection of combinations are included for all groups
herein.

[0220] In certain embodiments, a compound of Formula I, II, or III is a
selective TPO modulator. In certain embodiments, a compound of Formula I,
II, or III is a selective TPO receptor agonist. In certain embodiments, a
compound of Formula I, II, or III is a selective TPO receptor antagonist.
In certain embodiments, a compound of Formula I, II, or III is a
selective TPO receptor partial agonist. In certain embodiments, a
compound of Formula I, II, or III is a tissue-specific selective TPO
modulator. In certain embodiments, a compound of Formula I, II, or III is
a selective TPO receptor binding compound. In certain embodiments, a
compound of Formula I, II, or III is a TPO mimic.

[0221] In certain embodiments, the invention provides compounds including,
but not limited to:

[0435] 4-(4-{N'-[1-(3,4-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydr-
oindol-3-ylidene]hydrazino}-3-hydroxyphenyl)butanoic acid (Compound 310);
and a pharmaceutically acceptable salt ester, amide or prodrug of any of
those compounds.

[0436] In certain embodiments, the present invention provides any single
compound selected from any of the above lists of compounds. In certain
embodiments, the present invention provides any number and any
combination of compounds selected from the above lists of compounds.

[0437] Certain compounds of the present inventions may exist as
stereoisomers including optical isomers. The present disclosure is
intended to include all stereoisomers and both the racemic mixtures of
such stereoisomers as well as the individual enantiomers that may be
separated according to methods that are known in the art or that may be
excluded by synthesis schemes known in the art designed to yield
predominantly one enantomer relative to another.

Certain Synthesis Methods

[0438] In certain embodiments, certain compounds of the present invention
can by synthesized using the following Schemes.

[0439] The process of Scheme I is a multi-step synthetic sequence that
commences with the palladium catalyzed cross-coupling of a phenylboronic
acid such as structure 2 and an aryl bromide such as structure I to form
the biaryl structure 3. Deprotection of the methyl ether is followed by
nitration and hydrogenation to give the biphenyl amino acid such as
structure 4. The amino group is then diazotized under standard conditions
and is treated with the appropriate coupling partner to give the final
product of structure 6.

[0440] The process of Scheme II is a multi-step synthetic sequence that
commences with the copper catalyzed cross-coupling of an oxindole such as
structure 7 and an aryl or alkyl bromide to provide an N-substituted
oxindole of structure 8. This is then followed by coupling the
N-substituted oxindole with the diazonium salt of the biphenyl amino acid
such as structure 4 to give the final product of structure 9.

[0441] The process of Scheme III is a multi-step synthetic sequence that
commences with the reductive amination of an aniline such as structure 10
with a benzaldehyde and conversion into the chloroacetanilide of
structure 11 with chloroacetyl chloride. Palladium catalyzed ring closure
gives the N-benzyl oxindole such as structure 12, which is then coupled
to the diazonium salt of the biphenyl amino acid of structure 4 to give
the final product of structure 9.

[0442] The process of Scheme IV is a multi-step synthetic sequence that
commences with the conversion of an amine of structure 13 into an N-aryl
rhodanine of structure 14 with bis(carboxymethyl)trithiocarbonate. The
rhodanine is then coupled to the diazonium salt of the biphenyl amino
acid such as structure 4 to give the final product of structure 15.

[0443] In Scheme V, a hyrdoxynitrobenzaldehyde such as structure 16 is
converted into either a cinnamate such as structure 17 or
thiazolidinedione derivative of structure 19. The requisite nitro-group
is reduced and then converted into a diazonium salt and coupled to the
corresponding N-aryl oxindole of structure 8 to give the final compound
of structure 20.

[0444] One of skill in the art will recognize that analogous synthesis
schemes may be used to synthesize similar compounds. One of skill will
recognize that compounds of the present invention may be synthesized
using other synthesis schemes. In certain embodiments, the invention
provides a salt corresponding to any of the compounds provided herein.

[0445] In certain embodiments, the invention provides a salt corresponding
to a selective TPO modulator. In certain embodiments, the invention
provides a salt corresponding to a selective TPO receptor binding agent.
In certain embodiments, a salt is obtained by reacting a compound with an
acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid, and the like. In certain
embodiments, a salt is obtained by reacting a compound with a base to
form a salt such as an ammonium salt, an alkali metal salt, such as a
sodium or a potassium salt, an alkaline earth metal salt, such as a
calcium or a magnesium salt, a salt of organic bases such as choline,
dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,
4-(2-hydroxyethyl)-morpholine, 1-(2-hydroxyethyl)-pyrrolidine,
ethanolamine and salts with amino acids such as arginine, lysine, and the
like. In certain embodiments, a salt is obtained by reacting a free acid
form of a selective TPO modulator or selective TPO binding agent with
multiple molar equivalents of a base, such as bis-sodium,
bis-ethanolamine, and the like.

[0447] In certain embodiments, one or more carbon atoms of a compound of
the present invention are replaced with silicon. See e.g., WO
03/037905A1; Tacke and Zilch, Endeavour, New Series, 10, 191-197 (1986);
and Bains and Tacke, Curr. Opin. Drug Discov Devel.
July:6(4):526-43(2003). In certain embodiments, compounds of the present
invention comprising one or more silicon atoms possess certain desired
properties, including, but not limited to, greater stability and/or
longer half-life in a patient, when compared to the same compound in
which none of the carbon atoms have been replaced with a silicon atom.

Certain Assays

[0448] In certain embodiments, compounds of the present invention may be
used in a any of a variety of assays. For example, compounds of the
present invention may be tested for potency as selective TPO modulators
in a luciferase assay, such as those described in Lamb, et al., Nucleic
Acids Research, 23: 3283-3289(1995) and/or Seidel et al., Proc. Nat.
Acad. Sci. USA; 92: 3041-3045 (1995).

[0449] Certain compounds of the present invention may be used in in vitro
proliferation and/or differentiation assays, such as those described by
Bartley et al., Cell, 77: 1117-1124 (1994) and/or Cwirla, et al.,
Science, 276: 1696-1699 (1997).

Certain Pharmaceutical Compositions

[0450] In certain embodiments, at least one selective TPO modulator, or
pharmaceutically acceptable salt, ester, amide, and/or prodrug thereof,
combined with one or more pharmaceutically acceptable carriers, forms a
pharmaceutical composition. Techniques for formulation and administration
of compounds of the present invention may be found for example, in
"Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa.,
18th edition, 1990.

[0451] In certain embodiments, a pharmaceutical composition comprising one
or more compounds of the present invention is prepared using known
techniques, including, but not limited to mixing, dissolving,
granulating, dragee-making, levigating, emulsifying, encapsulating,
entrapping or tabletting processes.

[0452] In certain embodiments, a pharmaceutical composition comprising one
or more compounds of the present invention is a liquid (e.g., a
suspension, elixir and/or solution). In certain of such embodiments, a
liquid pharmaceutical composition comprising one or more compounds of the
present invention is prepared using ingredients known in the art,
including, but not limited to, water, glycols, oils, alcohols, flavoring
agents, preservatives, and coloring agents.

[0453] In certain embodiments, a pharmaceutical composition comprising one
or more compounds of the present invention is a solid (e.g., a powder,
tablet, and/or capsule). In certain of such embodiments, a solid
pharmaceutical composition comprising one or more compounds of the
present invention is prepared using ingredients known in the art,
including, but not limited to, starches, sugars, diluents, granulating
agents, lubricants, binders, and disintegrating agents.

[0454] In certain embodiments, a pharmaceutical composition comprising one
or more compounds of the present invention is formulated as a depot
preparation. Certain such depot preparations are typically longer acting
than non-depot preparations. In certain embodiments, such preparations
are administered by implantation (for example subcutaneously or
intramuscularly) or by intramuscular injection. In certain embodiments,
depot preparations are prepared using suitable polymeric or hydrophobic
materials (for example an emulsion in an acceptable oil) or ion exchange
resins, or as sparingly soluble derivatives, for example, as a sparingly
soluble salt.

[0455] In certain embodiments, a pharmaceutical composition comprising one
or more compounds of the present invention comprises a delivery system.
Examples of delivery systems include, but are not limited to, liposomes
and emulsions. Certain delivery systems are useful for preparing certain
pharmaceutical compositions including those comprising hydrophobic
compounds. In certain embodiments, certain organic solvents such as
dimethylsulfoxide are used.

[0456] In certain embodiments, a pharmaceutical composition comprising one
or more compounds of the present invention comprises one or more
tissue-specific delivery molecules designed to deliver the one or more
compounds of the present invention to specific tissues or cell types. For
example, in certain embodiments, pharmaceutical compositions include
liposomes coated with a tissue-specific antibody.

[0457] In certain embodiments, a pharmaceutical composition comprising one
or more compounds of the present invention comprises a co-solvent system.
Certain of such co-solvent systems comprise, for example, benzyl alcohol,
a nonpolar surfactant, a water-miscible organic polymer, and an aqueous
phase. In certain embodiments, such co-solvent systems are used for
hydrophobic compounds. A non-limiting example of such a co-solvent system
is the VPD co-solvent system, which is a solution of absolute ethanol
comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant
Polysorbate 80.TM., and 65% w/v polyethylene glycol 300. The proportions
of such co-solvent systems may be varied considerably without
significantly altering their solubility and toxicity characteristics.
Furthermore, the identity of co-solvent components may be varied: for
example, other surfactants may be used instead of Polysorbate 80.TM.; the
fraction size of polyethylene glycol may be varied; other biocompatible
polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone;
and other sugars or polysaccharides may substitute for dextrose.

[0458] In certain embodiments, a pharmaceutical composition comprising one
or more compounds of the present invention comprises a sustained-release
system. A non-limiting example of such a sustained-release system is a
semi-permeable matrix of solid hydrophobic polymers. In certain
embodiments, sustained-release systems may, depending on their chemical
nature, release compounds over a period of hours, days, weeks or months.

[0459] In certain embodiments, a pharmaceutical composition comprising a
compound of the present invention is prepared for oral administration. In
certain of such embodiments, a pharmaceutical composition is formulated
by combining one or more compounds of the present invention with one or
more pharmaceutically acceptable carriers. Certain of such carriers
enable compounds of the invention to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, slurries, suspensions and the
like, for oral ingestion by a patient. In certain embodiments,
pharmaceutical compositions for oral use are obtained by mixing one or
more compounds of the present invention and one or more solid excipient.
Suitable excipients include, but are not limited to, fillers, such as
sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose
preparations such as, for example, maize starch, wheat starch, rice
starch, potato starch, gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or
polyvinylpyrrolidone (PVP). In certain embodiments, such a mixture is
optionally ground and auxiliaries are optionally added. In certain
embodiments, pharmaceutical compositions are formed to obtain tablets or
dragee cores. In certain embodiments, disintegrating agents (e.g.,
cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt
thereof, such as sodium alginate) are added.

[0461] In certain embodiments, pharmaceutical compositions for oral
administration are push-fit capsules made of gelatin. Certain of such
push-fit capsules comprise one or more compounds of the present invention
in admixture with one or more filler such as lactose, binders such as
starches, and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In certain embodiments, pharmaceutical
compositions for oral administration are soft, sealed capsules made of
gelatin and a plasticizer, such as glycerol or sorbitol. In certain soft
capsules, one or more compounds of the present invention are be dissolved
or suspended in suitable liquids, such as fatty oils, liquid paraffin, or
liquid polyethylene glycols. In addition, stabilizers may be added.

[0462] In certain embodiments, pharmaceutical compositions are prepared
for buccal administration. Certain of such pharmaceutical compositions
are tablets or lozenges formulated in conventional manner.

[0463] In certain embodiments, a pharmaceutical composition is prepared
for administration by injection (e.g., intravenous, subcutaneous,
intramuscular, etc.). In certain of such embodiments, a pharmaceutical
composition comprises a carrier and is formulated in aqueous solution,
such as water or physiologically compatible buffers such as Hanks's
solution, Ringer's solution, or physiological saline buffer. In certain
embodiments, other ingredients are included (e.g., ingredients that aid
in solubility or serve as preservatives). In certain embodiments,
injectable suspensions are prepared using appropriate liquid carriers,
suspending agents and the like. Certain pharmaceutical compositions for
injection are presented in unit dosage form, e.g., in ampoules or in
multi-dose containers. Certain pharmaceutical compositions for injection
are suspensions, solutions or emulsions in oily or aqueous vehicles, and
may contain formulatory agents such as suspending, stabilizing and/or
dispersing agents. Certain solvents suitable for use in pharmaceutical
compositions for injection include, but are not limited to, lipophilic
solvents and fatty oils, such as sesame oil, synthetic fatty acid esters,
such as ethyl oleate or triglycerides, and liposomes. Aqueous injection
suspensions may contain substances that increase the viscosity of the
suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
Optionally, such suspensions may also contain suitable stabilizers or
agents that increase the solubility of the compounds to allow for the
preparation of highly concentrated solutions.

[0464] In certain embodiments, a pharmaceutical composition is prepared
for transmucosal administration. In certain of such embodiments
penetrants appropriate to the barrier to be permeated are used in the
formulation. Such penetrants are generally known in the art.

[0465] In certain embodiments, a pharmaceutical composition is prepared
for administration by inhalation. Certain of such pharmaceutical
compositions for inhalation are prepared in the form of an aerosol spray
in a pressurized pack or a nebulizer. Certain of such pharmaceutical
compositions comprise a propellant, e.g., dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
other suitable gas. In certain embodiments using a pressurized aerosol,
the dosage unit may be determined with a valve that delivers a metered
amount. In certain embodiments, capsules and cartridges for use in an
inhaler or insufflator may be formulated. Certain of such formulations
comprise a powder mixture of a compound of the invention and a suitable
powder base such as lactose or starch.

[0466] In certain embodiments, a pharmaceutical composition is prepared
for rectal administration, such as a suppositories or retention enema.
Certain of such pharmaceutical compositions comprise known ingredients,
such as cocoa butter and/or other glycerides.

[0467] In certain embodiments, a pharmaceutical composition is prepared
for topical administration. Certain of such pharmaceutical compositions
comprise bland moisturizing bases, such as ointments or creams. Exemplary
suitable ointment bases include, but are not limited to, petrolatum,
petrolatum plus volatile silicones, lanolin and water in oil emulsions
such as Eucerin.TM., available from Beiersdorf (Cincinnati, Ohio).
Exemplary suitable cream bases include, but are not limited to, Nivea.TM.
Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream (USP),
Purpose Cream.TM., available from Johnson & Johnson (New Brunswick,
N.J.), hydrophilic ointment (USP) and Lubriderm.TM., available from
Pfizer (Morris Plains, N.J.).

[0468] In certain embodiments, a pharmaceutical composition comprising one
or more compounds of the present invention comprises an active ingredient
in a therapeutically effective amount. In certain embodiments, the
therapeutically effective amount is sufficient to prevent, alleviate or
ameliorate symptoms of a disease or to prolong the survival of the
subject being treated. Determination of a therapeutically effective
amount is well within the capability of those skilled in the art.

[0469] In certain embodiments, one or more compounds of the present
invention is formulated as a prodrug. In certain embodiments, upon in
vivo administration, a prodrug is chemically converted to the
biologically, pharmaceutically or therapeutically more active form of the
compound. In certain embodiments, prodrugs are useful because they are
easier to administer than the corresponding active form. For example, in
certain instances, a prodrug may be more bioavailable (e.g., through oral
administration) than is the corresponding active form. In certain
instances, a prodrug may have improved solubility compared to the
corresponding active form. In certain embodiments, prodrugs are less
water soluble than the corresponding active form. In certain instances,
such prodrugs possess superior transmittal across cell membranes, where
water solubility is detrimental to mobility. In certain embodiments, a
prodrug is an ester. In certain such embodiments, the ester is
metabolically hydrolyzed to carboxylic acid upon administration. In
certain instances the carboxylic acid containing compound is the
corresponding active form. In certain embodiments, a prodrug comprises a
short peptide (polyaminoacid) bound to an acid group. In certain of such
embodiments, the peptide is cleaved upon administration to form the
corresponding active form.

[0470] In certain embodiments, a prodrug is produced by modifying a
pharmaceutically active compound such that the active compound will be
regenerated upon in vivo administration. The prodrug can be designed to
alter the metabolic stability or the transport characteristics of a drug,
to mask side effects or toxicity, to improve the flavor of a drug or to
alter other characteristics or properties of a drug. By virtue of
knowledge of pharmacodynamic processes and drug metabolism in vivo, those
of skill in this art, once a pharmaceutically active compound is known,
can design prodrugs of the compound (see, e.g., Nogrady (1985) Medicinal
Chemistry A Biochemical Approach, Oxford University Press, New York,
pages 388-392).

[0471] In certain embodiments, a pharmaceutical composition comprising one
or more compounds of the present invention is useful for treating a
conditions or disorders in a mammalian, and particularly in a human,
patient. Suitable administration routes include, but are not limited to,
oral, rectal, transmucosal, intestinal, enteral, topical, suppository,
through inhalation, intrathecal, intraventricular, intraperitoneal,
intranasal, intraocular and parenteral (e.g., intravenous, intramuscular,
intramedullary, and subcutaneous). In certain embodiments, pharmaceutical
intrathecals are administered to achieve local rather than systemic
exposures. For example, pharmaceutical compositions may be injected
directly in the area of desired effect (e.g., in the renal or cardiac
area).

[0472] In certain embodiments, a pharmaceutical composition comprising one
or more compounds of the present invention is administered in the form of
a dosage unit (e.g., tablet, capsule, bolus, etc.). In certain
embodiments, such dosage units comprise a selective TPO modulator in a
dose from about 1 .mu.g/kg of body weight to about 50 mg/kg of body
weight. In certain embodiments, such dosage units comprise a selective
TPO modulator in a dose from about 2 .mu.g/kg of body weight to about 25
mg/kg of body weight. In certain embodiments, such dosage units comprise
a selective TPO modulator in a dose from about 10 .mu.g/kg of body weight
to about 5 mg/kg of body weight. In certain embodiments, pharmaceutical
compositions are administered as needed, once per day, twice per day,
three times per day, or four or more times per day. It is recognized by
those skilled in the art that the particular dose, frequency, and
duration of administration depends on a number of factors, including,
without limitation, the biological activity desired, the condition of the
patient, and tolerance for the pharmaceutical composition.

[0473] In certain embodiments, the formulation, route of administration
and dosage for a pharmaceutical composition of the present invention can
be chosen in view of a particular patient's condition. (See e.g., Fingl
et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1).
In certain embodiments, a pharmaceutical composition is administered as a
single dose. In certain embodiments, a pharmaceutical composition is
administered as a series of two or more doses administered over one or
more days.

[0474] In certain embodiments, a pharmaceutical composition of the present
invention is administered to a patient between about 0.1% and 500%, more
preferably between about 25% and 75% of an established human dosage.
Where no human dosage is established, a suitable human dosage may be
inferred from ED.sub.50 or ID.sub.50 values, or other appropriate values
derived from in vitro or in vivo studies.

[0475] In certain embodiments, a daily dosage regimen for a patient
comprises an oral dose of between 0.1 mg and 2000 mg of a compound of the
present invention. In certain embodiments, a daily dosage regimen is
administered as a single daily dose. In certain embodiments, a daily
dosage regimen is administered as two, three, four, or more than four
doses.

[0476] In certain embodiments, a pharmaceutical composition of the present
invention is administered by continuous intravenous infusion. In certain
of such embodiments, from 0.1 mg to 500 mg of a composition of the
present invention is administered per day.

[0477] In certain embodiments, a pharmaceutical composition of the
invention is administered for a period of continuous therapy. For
example, a pharmaceutical composition of the present invention may be
administered over a period of days, weeks, months, or years.

[0478] Dosage amount, interval between doses, and duration of treatment
may be adjusted to achieve a desired effect. In certain embodiments,
dosage amount and interval between doses are adjusted to maintain a
desired concentration on compound in a patient. For example, in certain
embodiments, dosage amount and interval between doses are adjusted to
provide plasma concentration of a compound of the present invention at an
amount sufficient to achieve a desired effect. In certain of such
embodiments the plasma concentration is maintained above the minimal
effective concentration (MEC). In certain embodiments, pharmaceutical
compositions of the present invention are administered with a dosage
regimen designed to maintain a concentration above the MEC for 10-90% of
the time, between 30-90% of the time, or between 50-90% of the time.

[0479] In certain embodiments in which a pharmaceutical composition is
administered locally, the dosage regimen is adjusted to achieve a desired
local concentration of a compound of the present invention.

[0480] In certain embodiments, a pharmaceutical composition may be
presented in a pack or dispenser device which may contain one or more
unit dosage forms containing the active ingredient. The pack may for
example comprise metal or plastic foil, such as a blister pack. The pack
or dispenser device may be accompanied by instructions for
administration. The pack or dispenser may also be accompanied with a
notice associated with the container in form prescribed by a governmental
agency regulating the manufacture, use, or sale of pharmaceuticals, which
notice is reflective of approval by the agency of the form of the drug
for human or veterinary administration. Such notice, for example, may be
the labeling approved by the U.S. Food and Drug Administration for
prescription drugs, or the approved product insert. Compositions
comprising a compound of the invention formulated in a compatible
pharmaceutical carrier may also be prepared, placed in an appropriate
container, and labeled for treatment of an indicated condition.

[0481] In certain embodiments, a pharmaceutical composition is in powder
form for constitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.

Certain Combination Therapies

[0482] In certain embodiments, one or more pharmaceutical compositions of
the present invention are co-administered with one or more other
pharmaceutical agents. In certain embodiments, such one or more other
pharmaceutical agents are designed to treat the same disease or condition
as the one or more pharmaceutical compositions of the present invention.
In certain embodiments, such one or more other pharmaceutical agents are
designed to treat a different disease or condition as the one or more
pharmaceutical compositions of the present invention. In certain
embodiments, such one or more other pharmaceutical agents are designed to
treat an undesired effect of one or more pharmaceutical compositions of
the present invention. In certain embodiments, one or more pharmaceutical
compositions of the present invention are co-administered with another
pharmaceutical agent to treat an undesired effect of that other
pharmaceutical agent. In certain embodiments, one or more pharmaceutical
compositions of the present invention and one or more other
pharmaceutical agents are administered at the same time. In certain
embodiments, one or more pharmaceutical compositions of the present
invention and one or more other pharmaceutical agents are administered at
the different times. In certain embodiments, one or more pharmaceutical
compositions of the present invention and one or more other
pharmaceutical agents are prepared together in a single formulation. In
certain embodiments, one or more pharmaceutical compositions of the
present invention and one or more other pharmaceutical agents are
prepared separately.

[0484] In certain embodiments, the invention provides methods of treating
a patient comprising administering one or more compounds of the present
invention. In certain embodiments, such patient suffers from
thrombocytopenia. In certain such embodiments, thrombocytopenia results
from chemotherapy and/or radiation treatment. In certain embodiments,
thrombocytopenia results bone marrow failure resulting from bone marrow
transplantation and/or aplastic anemia. In certain embodiments
thrombocytopenia is idiopathic. In certain embodiments, one or more
compounds of the present invention are administered to a patient to in
conjunction with harvesting peripheral blood progenitor cells and/or in
conjunction with platelet apheresis. Such administration may be done
before, during, and/or after such harvesting.

[0485] In certain embodiments, one or more compounds of the present
invention are administered to a patient who suffers from a condition
affecting the nervous system, including, but are not limited to, diseases
affecting the nervous system and injuries to the nervous system. Such
diseases, include, but not limited to, amyotrophic lateral sclerosis,
multiple sclerosis, and multiple dystrophy. Injury to the nervous system
include, but are not limited to spinal cord injury or peripheral nerve
damage, including, but not limited to, injury resulting from trauma or
from stroke. In certain embodiments, one or more compounds of the present
invention are used to promote growth and/or development of glial cells.
Such glial cells may repair nerve cells. In certain embodiments,
compounds of the present invention are used to treat psychological
disorders, including, but not limited to, cognitive disorders. In certain
embodiments, one or more compounds of the invention are administered to
enhance athletic performance.

EXAMPLES

[0486] The following examples, including experiments and results achieved,
are provided for illustrative purposes only and are not to be construed
as limiting the present invention.